diff --git "a/SETH-test.iob" "b/SETH-test.iob"
new file mode 100644--- /dev/null
+++ "b/SETH-test.iob"
@@ -0,0 +1,26847 @@
+Word,Tag
+#23159251
+An,O
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+procedure,O
+for,O
+set,O
+-,O
+based,O
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+in,O
+sequencing,O
+studies,O
+.,O
+ , 
+State,O
+-,O
+of,O
+-,O
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+-,O
+art,O
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+-,O
+generation,O
+-,O
+sequencing,O
+technologies,O
+can,O
+facilitate,O
+in,O
+-,O
+depth,O
+explorations,O
+of,O
+the,O
+human,O
+genome,O
+by,O
+investigating,O
+both,O
+common,O
+and,O
+rare,O
+variants,O
+.,O
+ , 
+For,O
+the,O
+identification,O
+of,O
+genetic,O
+factors,O
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+are,O
+associated,O
+with,O
+disease,O
+risk,O
+or,O
+other,O
+complex,O
+phenotypes,O
+,,O
+methods,O
+have,O
+been,O
+proposed,O
+for,O
+jointly,O
+analyzing,O
+variants,O
+in,O
+a,O
+set,O
+(,O
+e.g.,O
+,,O
+all,O
+coding,O
+SNPs,O
+in,O
+a,O
+gene,O
+),O
+.,O
+ , 
+Variants,O
+in,O
+a,O
+properly,O
+defined,O
+set,O
+could,O
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+associated,O
+with,O
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+a,O
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+fashion,O
+,,O
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+by,O
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+from,O
+them,O
+,,O
+one,O
+can,O
+improve,O
+power,O
+to,O
+detect,O
+genetic,O
+risk,O
+factors,O
+.,O
+ , 
+Many,O
+set,O
+-,O
+based,O
+methods,O
+in,O
+the,O
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+based,O
+on,O
+statistics,O
+that,O
+can,O
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+written,O
+as,O
+the,O
+summation,O
+of,O
+variant,O
+statistics,O
+.,O
+ , 
+Here,O
+,,O
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+taking,O
+the,O
+summation,O
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+the,O
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+variant,O
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+as,O
+the,O
+set,O
+summary,O
+for,O
+association,O
+testing,O
+.,O
+ , 
+From,O
+both,O
+Bayesian,O
+and,O
+frequentist,O
+perspectives,O
+,,O
+we,O
+provide,O
+theoretical,O
+justification,O
+for,O
+taking,O
+the,O
+sum,O
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+,,O
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+the,O
+large,O
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+tested,O
+in,O
+a,O
+set,O
+,,O
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+variants,O
+are,O
+associated,O
+with,O
+disease,O
+risk,O
+-,O
+a,O
+distinctive,O
+feature,O
+of,O
+genetic,O
+data,O
+.,O
+ , 
+We,O
+applied,O
+the,O
+exponential,O
+combination,O
+gene,O
+-,O
+based,O
+test,O
+to,O
+a,O
+sequencing,O
+study,O
+in,O
+anticancer,O
+pharmacogenomics,O
+and,O
+uncovered,O
+mechanistic,O
+insights,O
+into,O
+genes,O
+and,O
+pathways,O
+related,O
+to,O
+chemotherapeutic,O
+susceptibility,O
+for,O
+an,O
+important,O
+class,O
+of,O
+oncologic,O
+drugs,O
+.,O
+ , 
+#8318995
+Sporadic,O
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+,,O
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+a,O
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+,,O
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+-,O
+thalassemia,O
+in,O
+Ashkenazi,O
+Jews,O
+.,O
+ , 
+#9452104
+Identification,O
+of,O
+four,O
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+the,O
+factor,B-Gene
+VIII,I-Gene
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+(,B-SNP
+E1875,I-SNP
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+1780delTC,I-SNP
+),I-SNP
+.,O
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+#21665001
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+,,O
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+mutations,O
+in,O
+PLCD1,B-Gene
+.,I-Gene
+ , 
+Hereditary,O
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+rare,O
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+an,O
+unknown,O
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+basis,O
+.,O
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+To,O
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+a,O
+gene,O
+underlying,O
+this,O
+phenotype,O
+,,O
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+four,O
+families,O
+of,O
+Pakistani,O
+origin,O
+showing,O
+features,O
+of,O
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+.,O
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+All,O
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+,,O
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+total,O
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+,,O
+with,O
+no,O
+other,O
+cutaneous,O
+,,O
+appendageal,O
+,,O
+or,O
+systemic,O
+findings,O
+.,O
+ , 
+By,O
+using,O
+Affymetrix,O
+10,O
+K,O
+chip,O
+,,O
+we,O
+established,O
+linkage,O
+to,O
+chromosome,O
+3p21.3,O
+-,O
+p22,O
+with,O
+a,O
+LOD,O
+score,O
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+Z,O
+),O
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+5.1,O
+.,O
+ , 
+We,O
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+pathogenic,O
+mutations,O
+in,O
+PLCD1,B-Gene
+in,O
+all,O
+four,O
+families,O
+,,O
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+encodes,O
+phosphoinositide,B-Gene
+-,I-Gene
+specific,I-Gene
+phospholipase,I-Gene
+C,I-Gene
+delta,I-Gene
+1,I-Gene
+subunit,O
+,,O
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+key,O
+enzyme,O
+in,O
+phosphoinositide,O
+metabolism,O
+.,O
+ , 
+We,O
+then,O
+identified,O
+localization,O
+of,O
+PLCD1,B-Gene
+in,O
+the,O
+nail,O
+matrix,O
+.,O
+ , 
+It,O
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+recently,O
+shown,O
+that,O
+PLCD1,B-Gene
+is,O
+a,O
+component,O
+of,O
+the,O
+human,O
+nail,O
+plate,O
+by,O
+proteomic,O
+analysis,O
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+is,O
+localized,O
+in,O
+the,O
+matrix,O
+of,O
+human,O
+nails,O
+.,O
+ , 
+Furthermore,O
+,,O
+mutations,O
+detected,O
+in,O
+PLCD1,B-Gene
+resulted,O
+in,O
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+enzymatic,O
+activity,O
+in,O
+ ,O
+vitro,O
+.,O
+ , 
+Our,O
+data,O
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+that,O
+mutations,O
+in,O
+PLCD1,B-Gene
+underlie,O
+hereditary,O
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+,,O
+revealing,O
+a,O
+gene,O
+involved,O
+in,O
+molecular,O
+control,O
+of,O
+nail,O
+growth,O
+.,O
+ , 
+#8940261
+The,O
+extent,O
+,,O
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+,,O
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+#20206336
+Identification,O
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+recurrent,O
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+by,O
+segmental,O
+duplications,O
+associated,O
+with,O
+heart,O
+defects,O
+and,O
+limb,O
+abnormalities,O
+.,O
+ , 
+Segmental,O
+duplications,O
+,,O
+which,O
+comprise,O
+approximately,O
+5%-10,O
+%,O
+of,O
+the,O
+human,O
+genome,O
+,,O
+are,O
+known,O
+to,O
+mediate,O
+medically,O
+relevant,O
+deletions,O
+,,O
+duplications,O
+,,O
+and,O
+inversions,O
+through,O
+nonallelic,O
+homologous,O
+recombination,O
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+NAHR,O
+),O
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+been,O
+suggested,O
+to,O
+be,O
+hot,O
+spots,O
+in,O
+chromosome,O
+evolution,O
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+human,O
+genomic,O
+instability,O
+.,O
+ , 
+We,O
+report,O
+seven,O
+individuals,O
+with,O
+microdeletions,O
+at,O
+17q23.1q23.2,O
+,,O
+identified,O
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+microarray,O
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+genomic,O
+hybridization,O
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+aCGH,O
+),O
+.,O
+ , 
+Six,O
+of,O
+the,O
+seven,O
+deletions,O
+are,O
+approximately,O
+2.2,O
+Mb,O
+in,O
+size,O
+and,O
+flanked,O
+by,O
+large,O
+segmental,O
+duplications,O
+of,O
+>,O
+98,O
+%,O
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+the,O
+same,O
+orientation,O
+.,O
+ , 
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+These,O
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+.,O
+ , 
+Although,O
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+least,O
+mild,O
+dysmorphic,O
+facial,O
+features,O
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+a,O
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+The,O
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+clinical,O
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+TBX2,B-Gene
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+,,I-Gene
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+family,O
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+genes,O
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+in,O
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+variety,O
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+developmental,O
+pathways,O
+including,O
+those,O
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+heart,O
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+,,O
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+these,O
+genes,O
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+an,O
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+.,O
+ , 
+#22365152
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+which,O
+discovery,O
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+underlying,O
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+Asn1768Asp,I-SNP
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+),O
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+Nav1.6,O
+,,O
+one,O
+of,O
+the,O
+most,O
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+brain,O
+.,O
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+Analysis,O
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+sodium,O
+current,O
+,,O
+incomplete,O
+channel,O
+inactivation,O
+,,O
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+a,O
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+in,O
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+voltage,O
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+-,O
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+.,O
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+Current,O
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+transfected,O
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+p.,B-SNP
+Asn1768Asp,I-SNP
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+,,O
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+-,O
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+-,O
+like,O
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+,,O
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+frequency,O
+,,O
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+a,O
+dominant,O
+gain,O
+-,O
+of,O
+-,O
+function,O
+phenotype,O
+in,O
+the,O
+heterozygous,O
+proband,O
+.,O
+ , 
+This,O
+work,O
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+SCN8A,B-Gene
+as,O
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+fifth,O
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+-,O
+channel,O
+gene,O
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+mutated,O
+in,O
+epilepsy,O
+and,O
+demonstrates,O
+the,O
+value,O
+of,O
+WGS,O
+for,O
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+identification,O
+of,O
+pathogenic,O
+mutations,O
+causing,O
+severe,O
+,,O
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+neurological,O
+disorders,O
+.,O
+ , 
+#12204007
+Identification,O
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+Bruton,B-Gene
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+tyrosine,I-Gene
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+BTK,I-Gene
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+patients,O
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+X,O
+-,O
+linked,O
+agammaglobulinemia,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+Bruton,B-Gene
+tyrosine,I-Gene
+kinase,I-Gene
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+BTK,I-Gene
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+gene,O
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+responsible,O
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+linked,O
+agammaglobulinemia,O
+(,O
+XLA,O
+),O
+,,O
+which,O
+is,O
+characterized,O
+by,O
+recurrent,O
+bacterial,O
+infections,O
+,,O
+profound,O
+hypogammaglobulinemia,O
+,,O
+and,O
+decreased,O
+numbers,O
+of,O
+mature,O
+B,O
+cells,O
+in,O
+the,O
+peripheral,O
+blood,O
+.,O
+ , 
+We,O
+evaluated,O
+17,O
+male,O
+Brazilian,O
+patients,O
+from,O
+13,O
+unrelated,O
+families,O
+who,O
+showed,O
+markedly,O
+reduced,O
+numbers,O
+of,O
+blood,O
+B,O
+cells,O
+and,O
+hypogammaglobulinemia,O
+.,O
+ , 
+BTK,B-Gene
+gene,O
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+detected,O
+mutations,O
+in,O
+10,O
+of,O
+the,O
+13,O
+presumed,O
+XLA,O
+families,O
+.,O
+ , 
+Seven,O
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+(,B-SNP
+Q196X,I-SNP
+,,I-SNP
+G613D,B-SNP
+,,I-SNP
+R28L,B-SNP
+,,I-SNP
+251,B-SNP
+-,I-SNP
+273del,I-SNP
+,,I-SNP
+Q234X,B-SNP
+,,I-SNP
+H364P,B-SNP
+,,I-SNP
+and,O
+R13X,B-SNP
+),I-SNP
+had,O
+been,O
+reported,O
+previously,O
+,,O
+whereas,O
+the,O
+remaining,O
+three,O
+mutations,O
+(,B-SNP
+M501,I-SNP
+T,I-SNP
+,,I-SNP
+IVS15,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+and,O
+IVS14,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
+were,O
+novel,O
+.,O
+ , 
+Mutation,O
+IVS15,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+C,I-SNP
+occurred,O
+in,O
+a,O
+splice,O
+donor,O
+site,O
+and,O
+caused,O
+exons,O
+15,O
+and,O
+16,O
+to,O
+be,O
+skipped,O
+,,O
+and,O
+IVS14,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+A,I-SNP
+might,O
+cause,O
+exon,O
+14,O
+to,O
+be,O
+skipped,O
+.,O
+ , 
+Flow,O
+cytometry,O
+revealed,O
+deficient,O
+expression,O
+of,O
+BTK,B-Gene
+protein,O
+in,O
+10,O
+of,O
+the,O
+13,O
+families,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+the,O
+diagnosis,O
+of,O
+XLA,O
+by,O
+analysis,O
+of,O
+mutations,O
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+BTK,B-Gene
+gene,O
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+Brazilian,O
+patients,O
+.,O
+ , 
+#9915968
+The,O
+Glu318Gly,B-SNP
+substitution,O
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+presenilin,B-Gene
+1,I-Gene
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+related,O
+to,O
+Alzheimer,O
+disease,O
+.,O
+ , 
+#22795537
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+novo,O
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+in,O
+MLL,B-Gene
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+-,O
+Steiner,O
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+.,O
+ , 
+Excessive,O
+growth,O
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+terminal,O
+hair,O
+around,O
+the,O
+elbows,O
+(,O
+hypertrichosis,O
+cubiti,O
+),O
+has,O
+been,O
+reported,O
+both,O
+in,O
+isolation,O
+and,O
+in,O
+association,O
+with,O
+a,O
+variable,O
+spectrum,O
+of,O
+associated,O
+phenotypic,O
+features,O
+.,O
+ , 
+We,O
+identified,O
+a,O
+cohort,O
+of,O
+six,O
+individuals,O
+with,O
+hypertrichosis,O
+cubiti,O
+associated,O
+with,O
+short,O
+stature,O
+,,O
+intellectual,O
+disability,O
+,,O
+and,O
+a,O
+distinctive,O
+facial,O
+appearance,O
+,,O
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+with,O
+a,O
+diagnosis,O
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+Wiedemann,O
+-,O
+Steiner,O
+syndrome,O
+(,O
+WSS,O
+),O
+.,O
+ , 
+Utilizing,O
+a,O
+whole,O
+-,O
+exome,O
+sequencing,O
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+,,O
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+identified,O
+de,O
+novo,O
+mutations,O
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+MLL,B-Gene
+in,O
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+of,O
+the,O
+six,O
+individuals,O
+.,O
+ , 
+MLL,B-Gene
+encodes,O
+a,O
+histone,O
+methyltransferase,O
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+regulates,O
+chromatin,O
+-,O
+mediated,O
+transcription,O
+through,O
+the,O
+catalysis,O
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+methylation,O
+of,O
+histone,O
+H3K4,O
+.,O
+ , 
+Each,O
+of,O
+the,O
+five,O
+mutations,O
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+predicted,O
+to,O
+result,O
+in,O
+premature,O
+termination,O
+of,O
+the,O
+protein,O
+product,O
+.,O
+ , 
+Furthermore,O
+,,O
+we,O
+demonstrate,O
+that,O
+transcripts,O
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+from,O
+the,O
+mutant,O
+alleles,O
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+subject,O
+to,O
+nonsense,O
+-,O
+mediated,O
+decay,O
+.,O
+ , 
+These,O
+findings,O
+define,O
+the,O
+genetic,O
+basis,O
+of,O
+WSS,O
+,,O
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+additional,O
+evidence,O
+for,O
+the,O
+role,O
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+,,O
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+the,O
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+of,O
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+modification,O
+in,O
+development,O
+.,O
+ , 
+#12740763
+Identification,O
+of,O
+a,O
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+gene,O
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+a,O
+common,O
+variant,O
+associated,O
+with,O
+uric,O
+acid,O
+nephrolithiasis,O
+in,O
+a,O
+Sardinian,O
+genetic,O
+isolate,O
+.,O
+ , 
+Uric,O
+acid,O
+nephrolithiasis,O
+(,O
+UAN,O
+),O
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+a,O
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+established,O
+genetic,O
+component,O
+that,O
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+a,O
+complex,O
+mode,O
+of,O
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+.,O
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+While,O
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+ancient,O
+founder,O
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+,,O
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+a,O
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+locus,O
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+approximately,O
+2.5,O
+cM,O
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+UAN,O
+on,O
+10q21,O
+-,O
+q22,O
+in,O
+a,O
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+small,O
+sample,O
+that,O
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+genealogical,O
+information,O
+.,O
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+To,O
+refine,O
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+gene,O
+,,O
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+extended,O
+our,O
+analysis,O
+to,O
+severely,O
+affected,O
+subjects,O
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+the,O
+same,O
+village,O
+.,O
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+We,O
+confirm,O
+the,O
+involvement,O
+of,O
+this,O
+region,O
+in,O
+UAN,O
+through,O
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+-,O
+by,O
+-,O
+descent,O
+sharing,O
+and,O
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+mapping,O
+,,O
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+we,O
+refine,O
+the,O
+critical,O
+region,O
+to,O
+an,O
+interval,O
+of,O
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+67,O
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+mapping,O
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+After,O
+inspecting,O
+the,O
+genomic,O
+sequences,O
+available,O
+in,O
+public,O
+databases,O
+,,O
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+that,O
+a,O
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+gene,O
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+this,O
+interval,O
+.,O
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+This,O
+gene,O
+is,O
+divided,O
+into,O
+15,O
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+,,O
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+a,O
+region,O
+of,O
+approximately,O
+300,O
+kb,O
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+generating,O
+at,O
+least,O
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+different,O
+proteins,O
+(,O
+407,O
+,,O
+333,O
+,,O
+462,O
+,,O
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+216,O
+amino,O
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+),O
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+Interestingly,O
+,,O
+the,O
+last,O
+isoform,O
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+completely,O
+included,O
+in,O
+the,O
+67,O
+-,O
+kb,O
+associated,O
+interval,O
+.,O
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+Computer,O
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+assisted,O
+analysis,O
+of,O
+this,O
+isoform,O
+revealed,O
+at,O
+least,O
+one,O
+membrane,O
+-,O
+spanning,O
+domain,O
+and,O
+several,O
+N-,O
+and,O
+O,O
+-,O
+glycosylation,O
+consensus,O
+sites,O
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+N,O
+-,O
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+,,O
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+that,O
+it,O
+could,O
+be,O
+an,O
+integral,O
+membrane,O
+protein,O
+.,O
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+Mutational,O
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+(,B-SNP
+Ala62Thr,I-SNP
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+,,O
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+a,O
+missense,O
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+12,O
+,,O
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+UAN,O
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+Moreover,O
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+Ala62Thr,B-SNP
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+protein,O
+secondary,O
+structure,O
+,,O
+suggesting,O
+that,O
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+a,O
+role,O
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+etiology,O
+.,O
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+The,O
+present,O
+study,O
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+,,O
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+genes,O
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+complex,O
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+Indeed,O
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+#8352278
+Statistical,O
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+its,O
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+human,O
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+Common,O
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+,,O
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+ , 
+One,O
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+mapping,O
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+such,O
+traits,O
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+to,O
+first,O
+study,O
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+,,O
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+as,O
+mouse,O
+,,O
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+.,O
+ , 
+Here,O
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+describe,O
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+from,O
+such,O
+experimental,O
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+,,O
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+in,O
+light,O
+of,O
+multilocus,O
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+models,O
+,,O
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+effects,O
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+ , 
+We,O
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+these,O
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+by,O
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+backcrosses,O
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+mouse,O
+,,O
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+human,O
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+.,O
+ , 
+We,O
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+that,O
+it,O
+is,O
+likely,O
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+a,O
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+to,O
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+,,O
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+these,O
+loci,O
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+Three,O
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+,,O
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+the,O
+heterozygote,O
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+ , 
+Further,O
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+Specifically,O
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+,,O
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+,,O
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+the,O
+expected,O
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+human,O
+form,O
+,,O
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+in,O
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+gene,O
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+depend,O
+more,O
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+on,O
+disease,O
+allele,O
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+on,O
+the,O
+observed,O
+penetrance,O
+ratios,O
+;,O
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+allele,O
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+unpredictable,O
+.,O
+ , 
+Hence,O
+,,O
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+major,O
+benefit,O
+from,O
+animal,O
+studies,O
+may,O
+be,O
+a,O
+better,O
+understanding,O
+of,O
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+disease,O
+process,O
+itself,O
+,,O
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+cells,O
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+comparison,O
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+regions,O
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+.,O
+ , 
+#1609807
+Anticipation,O
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+rescue,O
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+#11951177
+High,O
+-,O
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+genomic,O
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+Telomeric,O
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+,,O
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+.,O
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+Automated,O
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+subtle,O
+deletions,O
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+duplications,O
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+telomeres,O
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+essential,O
+for,O
+high,O
+-,O
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+,,O
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+cytogenetic,O
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+.,O
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+Array,O
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+by,O
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+differentially,O
+labeled,O
+test,O
+and,O
+reference,O
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+clones,O
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+ , 
+To,O
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+of,O
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+the,O
+diagnosis,O
+of,O
+(,O
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+imbalances,O
+,,O
+we,O
+here,O
+describe,O
+a,O
+blinded,O
+study,O
+,,O
+in,O
+which,O
+DNA,O
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+20,O
+patients,O
+with,O
+known,O
+cytogenetic,O
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+involving,O
+one,O
+or,O
+more,O
+telomeres,O
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+hybridized,O
+to,O
+an,O
+array,O
+containing,O
+a,O
+validated,O
+set,O
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+human,O
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+-,O
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+(,O
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+Single,O
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+detected,O
+on,O
+these,O
+arrays,O
+,,O
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+the,O
+array,O
+-,O
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+CGH,O
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+of,O
+a,O
+single,O
+hybridization,O
+.,O
+ , 
+In,O
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+the,O
+previously,O
+identified,O
+cytogenetic,O
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+,,O
+array,O
+-,O
+based,O
+CGH,O
+revealed,O
+additional,O
+telomere,O
+rearrangements,O
+in,O
+3,O
+of,O
+the,O
+20,O
+patients,O
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+.,O
+ , 
+The,O
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+and,O
+simplicity,O
+of,O
+this,O
+array,O
+-,O
+based,O
+telomere,O
+copy,O
+-,O
+number,O
+screening,O
+make,O
+it,O
+highly,O
+suited,O
+for,O
+introduction,O
+into,O
+the,O
+clinic,O
+as,O
+a,O
+rapid,O
+and,O
+sensitive,O
+automated,O
+diagnostic,O
+procedure,O
+.,O
+ , 
+#11385711
+The,O
+R71,B-SNP
+G,I-SNP
+BRCA1,B-Gene
+is,O
+a,O
+founder,O
+Spanish,O
+mutation,O
+and,O
+leads,O
+to,O
+aberrant,O
+splicing,O
+of,O
+the,O
+transcript,O
+.,O
+ , 
+In,O
+a,O
+BRCA1,B-Gene
+screening,O
+in,O
+familial,O
+breast,O
+cancer,O
+carried,O
+out,O
+in,O
+different,O
+centres,O
+in,O
+Spain,O
+,,O
+France,O
+,,O
+and,O
+United,O
+Kingdom,O
+,,O
+a,O
+missense,O
+mutation,O
+330A,B-SNP
+>,I-SNP
+G,I-SNP
+which,O
+results,O
+in,O
+a,O
+Arg,B-SNP
+to,I-SNP
+Gly,I-SNP
+change,I-SNP
+at,I-SNP
+codon,I-SNP
+71,I-SNP
+(,B-SNP
+R71,I-SNP
+G,I-SNP
+),I-SNP
+was,O
+independently,O
+identified,O
+in,O
+6,O
+families,O
+,,O
+all,O
+of,O
+them,O
+with,O
+Spanish,O
+ancestors,O
+.,O
+ , 
+This,O
+residue,O
+coincides,O
+with,O
+the,O
+-2,O
+position,O
+of,O
+the,O
+exon,O
+5,O
+donor,O
+splice,O
+site,O
+.,O
+ , 
+We,O
+further,O
+investigated,O
+the,O
+effect,O
+of,O
+this,O
+base,O
+substitution,O
+on,O
+the,O
+splicing,O
+of,O
+BRCA1,B-Gene
+mRNA,O
+.,O
+ , 
+The,O
+sequence,O
+analysis,O
+of,O
+the,O
+cDNA,O
+indicated,O
+that,O
+22,O
+bp,O
+of,O
+exon,O
+5,O
+were,O
+deleted,O
+,,O
+creating,O
+with,O
+the,O
+first,O
+bases,O
+of,O
+exon,O
+6,O
+a,O
+termination,O
+codon,O
+at,O
+position,O
+64,O
+,,O
+which,O
+results,O
+in,O
+a,O
+truncated,O
+protein,O
+.,O
+ , 
+The,O
+BRCA1,B-Gene
+haplotype,O
+of,O
+the,O
+R71,B-SNP
+G,I-SNP
+carrier,O
+patients,O
+and,O
+Spanish,O
+controls,O
+was,O
+analysed,O
+by,O
+use,O
+of,O
+six,O
+microsatellites,O
+located,O
+within,O
+or,O
+near,O
+BRCA1,B-Gene
+.,I-Gene
+ , 
+Our,O
+results,O
+are,O
+consistent,O
+with,O
+the,O
+possibility,O
+that,O
+these,O
+families,O
+shared,O
+a,O
+common,O
+ancestry,O
+with,O
+BRCA1,B-Gene
+R71,B-SNP
+G,I-SNP
+being,O
+a,O
+founder,O
+mutation,O
+of,O
+Spanish,O
+origin,O
+.,O
+ , 
+#17160889
+Identification,O
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+a,O
+novel,O
+BBS,O
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+(,B-Gene
+BBS12,I-Gene
+),I-Gene
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+the,O
+major,O
+role,O
+of,O
+a,O
+vertebrate,O
+-,O
+specific,O
+branch,O
+of,O
+chaperonin,O
+-,O
+related,O
+proteins,O
+in,O
+Bardet,O
+-,O
+Biedl,O
+syndrome,O
+.,O
+ , 
+Bardet,O
+-,O
+Biedl,O
+syndrome,O
+(,O
+BBS,O
+),O
+is,O
+primarily,O
+an,O
+autosomal,O
+recessive,O
+ciliopathy,O
+characterized,O
+by,O
+progressive,O
+retinal,O
+degeneration,O
+,,O
+obesity,O
+,,O
+cognitive,O
+impairment,O
+,,O
+polydactyly,O
+,,O
+and,O
+kidney,O
+anomalies,O
+.,O
+ , 
+The,O
+disorder,O
+is,O
+genetically,O
+heterogeneous,O
+,,O
+with,O
+11,O
+BBS,O
+genes,O
+identified,O
+to,O
+date,O
+,,O
+which,O
+account,O
+for,O
+~70,O
+%,O
+of,O
+affected,O
+families,O
+.,O
+ , 
+We,O
+have,O
+combined,O
+single,O
+-,O
+nucleotide,O
+-,O
+polymorphism,O
+array,O
+homozygosity,O
+mapping,O
+with,O
+in,O
+silico,O
+analysis,O
+to,O
+identify,O
+a,O
+new,O
+BBS,O
+gene,O
+,,O
+BBS12,B-Gene
+.,I-Gene
+ , 
+Patients,O
+from,O
+two,O
+Gypsy,O
+families,O
+were,O
+homozygous,O
+and,O
+haploidentical,O
+in,O
+a,O
+6,O
+-,O
+Mb,O
+region,O
+of,O
+chromosome,O
+4q27,O
+.,O
+ , 
+FLJ35630,B-Gene
+was,O
+selected,O
+as,O
+a,O
+candidate,O
+gene,O
+,,O
+because,O
+it,O
+was,O
+predicted,O
+to,O
+encode,O
+a,O
+protein,O
+with,O
+similarity,O
+to,O
+members,O
+of,O
+the,O
+type,O
+II,O
+chaperonin,O
+superfamily,O
+,,O
+which,O
+includes,O
+BBS6,B-Gene
+and,O
+BBS10,B-Gene
+.,I-Gene
+ , 
+We,O
+found,O
+pathogenic,O
+mutations,O
+in,O
+both,O
+Gypsy,O
+families,O
+,,O
+as,O
+well,O
+as,O
+in,O
+14,O
+other,O
+families,O
+of,O
+various,O
+ethnic,O
+backgrounds,O
+,,O
+indicating,O
+that,O
+BBS12,B-Gene
+accounts,O
+for,O
+approximately,O
+5,O
+%,O
+of,O
+all,O
+BBS,O
+cases,O
+.,O
+ , 
+BBS12,B-Gene
+is,O
+vertebrate,O
+specific,O
+and,O
+,,O
+together,O
+with,O
+BBS6,B-Gene
+and,O
+BBS10,B-Gene
+,,I-Gene
+defines,O
+a,O
+novel,O
+branch,O
+of,O
+the,O
+type,O
+II,O
+chaperonin,O
+superfamily,O
+.,O
+ , 
+These,O
+three,O
+genes,O
+are,O
+characterized,O
+by,O
+unusually,O
+rapid,O
+evolution,O
+and,O
+are,O
+likely,O
+to,O
+perform,O
+ciliary,O
+functions,O
+specific,O
+to,O
+vertebrates,O
+that,O
+are,O
+important,O
+in,O
+the,O
+pathophysiology,O
+of,O
+the,O
+syndrome,O
+,,O
+and,O
+together,O
+they,O
+account,O
+for,O
+about,O
+one,O
+-,O
+third,O
+of,O
+the,O
+total,O
+BBS,O
+mutational,O
+load,O
+.,O
+ , 
+Consistent,O
+with,O
+this,O
+notion,O
+,,O
+suppression,O
+of,O
+each,O
+family,O
+member,O
+in,O
+zebrafish,O
+yielded,O
+gastrulation,O
+-,O
+movement,O
+defects,O
+characteristic,O
+of,O
+other,O
+BBS,O
+morphants,O
+,,O
+whereas,O
+simultaneous,O
+suppression,O
+of,O
+all,O
+three,O
+members,O
+resulted,O
+in,O
+severely,O
+affected,O
+embryos,O
+,,O
+possibly,O
+hinting,O
+at,O
+partial,O
+functional,O
+redundancy,O
+within,O
+this,O
+protein,O
+family,O
+.,O
+ , 
+#10094560
+Characterization,O
+of,O
+eleven,O
+novel,O
+mutations,O
+(,B-SNP
+M45L,I-SNP
+,,I-SNP
+R119H,B-SNP
+,,I-SNP
+544delG,B-SNP
+,,I-SNP
+G145V,B-SNP
+,,I-SNP
+H154Y,B-SNP
+,,I-SNP
+C184Y,B-SNP
+,,I-SNP
+D289V,B-SNP
+,,I-SNP
+862,B-SNP
++,I-SNP
+5A,I-SNP
+,,I-SNP
+1172delC,B-SNP
+,,I-SNP
+R411X,B-SNP
+,,I-SNP
+E459,B-SNP
+K,I-SNP
+),I-SNP
+in,O
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+tissue,B-Gene
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+(,B-Gene
+TNSALP,I-Gene
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+hypophosphatasia,O
+.,O
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+Mutations,O
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+no,O
+.,O
+217,O
+.,O
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+Online,O
+.,O
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+Hypophosphatasia,O
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+by,O
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+bone,O
+mineralization,O
+and,O
+deficiency,O
+of,O
+serum,O
+and,O
+tissue,O
+liver/,O
+bone,O
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+tissue,B-Gene
+alkaline,I-Gene
+phosphatase,I-Gene
+(,O
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+.,O
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+We,O
+report,O
+the,O
+characterization,O
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+tissue,B-Gene
+-,I-Gene
+nonspecific,I-Gene
+alkaline,I-Gene
+phosphatase,I-Gene
+(,B-Gene
+TNSALP,I-Gene
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+a,O
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+hypophosphatasia,O
+.,O
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+Fourteen,O
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+mutations,O
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+found,O
+,,O
+3,O
+of,O
+which,O
+were,O
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+reported,O
+in,O
+the,O
+North,O
+American,O
+or,O
+Japanese,O
+populations,O
+.,O
+ , 
+Seven,O
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+the,O
+11,O
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+(,B-SNP
+M45L,I-SNP
+,,I-SNP
+R119H,B-SNP
+,,I-SNP
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+C184Y,B-SNP
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+H154Y,B-SNP
+,,I-SNP
+D289V,B-SNP
+,,I-SNP
+E459,B-SNP
+K,I-SNP
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+544delG,I-SNP
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++,I-SNP
+5A,I-SNP
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+R411X,I-SNP
+),I-SNP
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+#8477262
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+We,O
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+searched,O
+for,O
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+choroideremia,B-Gene
+gene,O
+(,B-Gene
+CHM,I-Gene
+),I-Gene
+in,O
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+12,O
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+in,O
+which,O
+CHM,O
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+.,O
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+Employing,O
+polymerase,O
+chain,O
+reaction,O
+(,O
+PCR,O
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+,,O
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+strand,O
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+polymorphism,O
+(,O
+SSCP,O
+),O
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+direct,O
+DNA,O
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+6,O
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+All,O
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+the,O
+correct,O
+translation,O
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+the,O
+mRNA,O
+predicting,O
+a,O
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+protein,O
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+gene,O
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+all,O
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+#12673796
+Detection,O
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+enhanced,O
+PCR,O
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+RFLP,O
+approach,O
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+ , 
+Ethidium,O
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+-,O
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+,,O
+and,O
+is,O
+perhaps,O
+the,O
+simplest,O
+method,O
+for,O
+detection,O
+of,O
+known,O
+mutations,O
+in,O
+cancer,O
+-,O
+related,O
+genes,O
+and,O
+for,O
+genotyping,O
+a,O
+wide,O
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+human,O
+diseases,O
+.,O
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+However,O
+,,O
+its,O
+application,O
+is,O
+limited,O
+by,O
+the,O
+fact,O
+that,O
+it,O
+can,O
+only,O
+detect,O
+mutant,O
+alleles,O
+that,O
+are,O
+present,O
+in,O
+more,O
+than,O
+5,O
+-,O
+10,O
+%,O
+of,O
+wild,O
+-,O
+type,O
+alleles,O
+.,O
+ , 
+Here,O
+we,O
+present,O
+a,O
+method,O
+that,O
+allows,O
+a,O
+1,O
+-,O
+2,O
+order,O
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+in,O
+the,O
+sensitivity,O
+of,O
+the,O
+widely,O
+used,O
+PCR,O
+-,O
+RFLP,O
+without,O
+substantially,O
+increasing,O
+the,O
+effort,O
+and,O
+cost,O
+associated,O
+with,O
+it,O
+.,O
+ , 
+This,O
+method,O
+is,O
+a,O
+modification,O
+to,O
+our,O
+previously,O
+reported,O
+amplification,O
+via,O
+primer,O
+ligation,O
+at,O
+the,O
+mutation,O
+(,O
+APRIL,O
+-,O
+ATM,O
+),O
+method,O
+,,O
+which,O
+utilizes,O
+ligation,O
+of,O
+a,O
+primer,O
+at,O
+a,O
+restriction,O
+site,O
+formed,O
+by,O
+a,O
+mutation,O
+,,O
+followed,O
+by,O
+a,O
+ligation,O
+-,O
+mediated,O
+PCR,O
+amplification,O
+which,O
+amplifies,O
+only,O
+the,O
+mutation,O
+-,O
+containing,O
+DNA,O
+molecules,O
+.,O
+ , 
+By,O
+combining,O
+this,O
+method,O
+with,O
+the,O
+artificial,O
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+of,O
+restriction,O
+sites,O
+during,O
+PCR,O
+,,O
+we,O
+demonstrate,O
+that,O
+assays,O
+can,O
+be,O
+designed,O
+and,O
+validated,O
+for,O
+detecting,O
+hot,O
+-,O
+spot,O
+mutations,O
+in,O
+codons,O
+273,O
+,,O
+158,O
+,,O
+and,O
+248,O
+of,O
+the,O
+TP53,B-Gene
+gene,O
+(,B-Gene
+p53,I-Gene
+),I-Gene
+and,O
+potentially,O
+for,O
+most,O
+mutations,O
+of,O
+interest,O
+.,O
+ , 
+This,O
+approach,O
+is,O
+validated,O
+by,O
+using,O
+samples,O
+where,O
+the,O
+mutation,O
+was,O
+artificially,O
+introduced,O
+at,O
+these,O
+p53,O
+positions,B-Gene
+.,I-Gene
+ , 
+The,O
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+sensitivity,O
+offered,O
+by,O
+the,O
+method,O
+further,O
+allows,O
+us,O
+to,O
+rapidly,O
+screen,O
+for,O
+low,O
+frequency,O
+polymorphisms,O
+in,O
+pooled,O
+DNA,O
+samples,O
+.,O
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+The,O
+frequency,O
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+MSH2,B-Gene
+missense,O
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+(,B-SNP
+965G,I-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
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+in,O
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+genomic,O
+DNA,O
+samples,O
+from,O
+205,O
+and,O
+221,O
+U.S.,O
+and,O
+Polish,O
+colorectal,O
+cancer,O
+patients,O
+,,O
+respectively,O
+,,O
+and,O
+an,O
+equal,O
+number,O
+of,O
+ethnicity,O
+-,O
+matched,O
+controls,O
+.,O
+ , 
+The,O
+data,O
+revealed,O
+a,O
+3,O
+-,O
+5,O
+%,O
+prevalence,O
+of,O
+this,O
+polymorphism,O
+in,O
+the,O
+patient,O
+and,O
+the,O
+control,O
+populations,O
+.,O
+ , 
+Individual,O
+sequencing,O
+of,O
+all,O
+852,O
+patient,O
+samples,O
+demonstrated,O
+an,O
+excellent,O
+agreement,O
+among,O
+the,O
+two,O
+independent,O
+approaches,O
+.,O
+ , 
+The,O
+present,O
+enhanced,O
+PCR,O
+-,O
+RFLP,O
+reduces,O
+the,O
+effort,O
+involved,O
+in,O
+high,O
+throughput,O
+polymorphism,O
+studies,O
+and,O
+promises,O
+to,O
+find,O
+applications,O
+in,O
+genotyping,O
+and,O
+association,O
+studies,O
+involving,O
+low,O
+frequency,O
+polymorphisms,O
+and,O
+mutations,O
+.,O
+ , 
+#21473986
+Human,O
+and,O
+mouse,O
+mutations,O
+in,O
+WDR35,B-Gene
+cause,O
+short,O
+-,O
+rib,O
+polydactyly,O
+syndromes,O
+due,O
+to,O
+abnormal,O
+ciliogenesis,O
+.,O
+ , 
+Defects,O
+in,O
+cilia,O
+formation,O
+and,O
+function,O
+result,O
+in,O
+a,O
+range,O
+of,O
+human,O
+skeletal,O
+and,O
+visceral,O
+abnormalities,O
+.,O
+ , 
+Mutations,O
+in,O
+several,O
+genes,O
+have,O
+been,O
+identified,O
+to,O
+cause,O
+a,O
+proportion,O
+of,O
+these,O
+disorders,O
+,,O
+some,O
+of,O
+which,O
+display,O
+genetic,O
+(,O
+locus,O
+),O
+heterogeneity,O
+.,O
+ , 
+Mouse,O
+models,O
+are,O
+valuable,O
+for,O
+dissecting,O
+the,O
+function,O
+of,O
+these,O
+genes,O
+,,O
+as,O
+well,O
+as,O
+for,O
+more,O
+detailed,O
+analysis,O
+of,O
+the,O
+underlying,O
+developmental,O
+defects,O
+.,O
+ , 
+The,O
+short,O
+-,O
+rib,O
+polydactyly,O
+(,O
+SRP,O
+),O
+group,O
+of,O
+disorders,O
+are,O
+among,O
+the,O
+most,O
+severe,O
+human,O
+phenotypes,O
+caused,O
+by,O
+cilia,O
+dysfunction,O
+.,O
+ , 
+We,O
+mapped,O
+the,O
+disease,O
+locus,O
+from,O
+two,O
+siblings,O
+affected,O
+by,O
+a,O
+severe,O
+form,O
+of,O
+SRP,O
+to,O
+2p24,O
+,,O
+where,O
+we,O
+identified,O
+an,O
+in,O
+-,O
+frame,O
+homozygous,O
+deletion,O
+of,O
+exon,O
+5,O
+in,O
+WDR35,B-Gene
+.,I-Gene
+ , 
+We,O
+subsequently,O
+found,O
+compound,O
+heterozygous,O
+missense,O
+and,O
+nonsense,O
+mutations,O
+in,O
+WDR35,B-Gene
+in,O
+an,O
+independent,O
+second,O
+case,O
+with,O
+a,O
+similar,O
+,,O
+severe,O
+SRP,O
+phenotype,O
+.,O
+ , 
+In,O
+a,O
+mouse,O
+mutation,O
+screen,O
+for,O
+developmental,O
+phenotypes,O
+,,O
+we,O
+identified,O
+a,O
+mutation,O
+in,O
+Wdr35,B-Gene
+as,O
+the,O
+cause,O
+of,O
+midgestation,O
+lethality,O
+,,O
+with,O
+abnormalities,O
+characteristic,O
+of,O
+defects,O
+in,O
+the,O
+Hedgehog,O
+signaling,O
+pathway,O
+.,O
+ , 
+We,O
+show,O
+that,O
+endogenous,O
+WDR35,B-Gene
+localizes,O
+to,O
+cilia,O
+and,O
+centrosomes,O
+throughout,O
+the,O
+developing,O
+embryo,O
+and,O
+that,O
+human,O
+and,O
+mouse,O
+fibroblasts,O
+lacking,O
+the,O
+protein,O
+fail,O
+to,O
+produce,O
+cilia,O
+.,O
+ , 
+Through,O
+structural,O
+modeling,O
+,,O
+we,O
+show,O
+that,O
+WDR35,B-Gene
+has,O
+strong,O
+homology,O
+to,O
+the,O
+COPI,B-Gene
+coatamers,O
+involved,O
+in,O
+vesicular,O
+trafficking,O
+and,O
+that,O
+human,O
+SRP,O
+mutations,O
+affect,O
+key,O
+structural,O
+elements,O
+in,O
+WDR35,B-Gene
+.,I-Gene
+ , 
+Our,O
+report,O
+expands,O
+,,O
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+sheds,O
+new,O
+light,O
+on,O
+,,O
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+pathogenesis,O
+of,O
+the,O
+SRP,O
+spectrum,O
+of,O
+ciliopathies,O
+.,O
+ , 
+#11179018
+A,O
+phase,O
+1/2,O
+clinical,O
+trial,O
+of,O
+enzyme,O
+replacement,O
+in,O
+fabry,O
+disease,O
+:,O
+pharmacokinetic,O
+,,O
+substrate,O
+clearance,O
+,,O
+and,O
+safety,O
+studies,O
+.,O
+ , 
+Fabry,O
+disease,O
+results,O
+from,O
+deficient,O
+alpha,O
+-,O
+galactosidase,O
+A,O
+(,O
+alpha,O
+-,O
+Gal,O
+A,O
+),O
+activity,O
+and,O
+the,O
+pathologic,O
+accumulation,O
+of,O
+the,O
+globotriaosylceramide,O
+(,O
+GL-3,O
+),O
+and,O
+related,O
+glycosphingolipids,O
+,,O
+primarily,O
+in,O
+vascular,O
+endothelial,O
+lysosomes,O
+.,O
+ , 
+Treatment,O
+is,O
+currently,O
+palliative,O
+,,O
+and,O
+affected,O
+patients,O
+generally,O
+die,O
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+their,O
+40s,O
+or,O
+50s,O
+.,O
+ , 
+Preclinical,O
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+recombinant,O
+human,O
+alpha,B-Gene
+-,I-Gene
+Gal,I-Gene
+A,I-Gene
+(,B-Gene
+r,I-Gene
+-,I-Gene
+halphaGalA,I-Gene
+),I-Gene
+infusions,O
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+knockout,O
+mice,O
+demonstrated,O
+reduction,O
+of,O
+GL-3,B-Gene
+in,O
+tissues,O
+and,O
+plasma,O
+,,O
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+rationale,O
+for,O
+a,O
+phase,O
+1/2,O
+clinical,O
+trial,O
+.,O
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+Here,O
+,,O
+we,O
+report,O
+a,O
+single,O
+-,O
+center,O
+,,O
+open,O
+-,O
+label,O
+,,O
+dose,O
+-,O
+ranging,O
+study,O
+of,O
+r,B-Gene
+-,I-Gene
+halphaGalA,I-Gene
+treatment,O
+in,O
+15,O
+patients,O
+,,O
+each,O
+of,O
+whom,O
+received,O
+five,O
+infusions,O
+at,O
+one,O
+of,O
+five,O
+dose,O
+regimens,O
+.,O
+ , 
+Intravenously,O
+administered,O
+r,B-Gene
+-,I-Gene
+halphaGalA,I-Gene
+was,O
+cleared,O
+from,O
+the,O
+circulation,O
+in,O
+a,O
+dose,O
+-,O
+dependent,O
+manner,O
+,,O
+via,O
+both,O
+saturable,O
+and,O
+non,O
+-,O
+saturable,O
+pathways,O
+.,O
+ , 
+Rapid,O
+and,O
+marked,O
+reductions,O
+in,O
+plasma,O
+and,O
+tissue,O
+GL-3,B-Gene
+were,O
+observed,O
+biochemically,O
+,,O
+histologically,O
+,,O
+and/or,O
+ultrastructurally,O
+.,O
+ , 
+Clearance,O
+of,O
+plasma,O
+GL-3,B-Gene
+was,O
+dose,O
+-,O
+dependent,O
+.,O
+ , 
+In,O
+patients,O
+with,O
+pre-,O
+and,O
+posttreatment,O
+biopsies,O
+,,O
+mean,O
+GL-3,B-Gene
+content,O
+decreased,O
+84,O
+%,O
+in,O
+liver,O
+(,O
+n=13,O
+),O
+,,O
+was,O
+markedly,O
+reduced,O
+in,O
+kidney,O
+in,O
+four,O
+of,O
+five,O
+patients,O
+,,O
+and,O
+after,O
+five,O
+doses,O
+was,O
+modestly,O
+lowered,O
+in,O
+the,O
+endomyocardium,O
+of,O
+four,O
+of,O
+seven,O
+patients,O
+.,O
+ , 
+GL-3,B-Gene
+ , 
+deposits,O
+were,O
+cleared,O
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+near,O
+normal,O
+or,O
+were,O
+markedly,O
+reduced,O
+in,O
+the,O
+vascular,O
+endothelium,O
+of,O
+liver,O
+,,O
+skin,O
+,,O
+heart,O
+,,O
+and,O
+kidney,O
+,,O
+on,O
+the,O
+basis,O
+of,O
+light-,O
+and,O
+electron,O
+-,O
+microscopic,O
+evaluation,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+patients,O
+reported,O
+less,O
+pain,O
+,,O
+increased,O
+ability,O
+to,O
+sweat,O
+,,O
+and,O
+improved,O
+quality,O
+-,O
+of,O
+-,O
+life,O
+measures,O
+.,O
+ , 
+Infusions,O
+were,O
+well,O
+tolerated,O
+;,O
+four,O
+patients,O
+experienced,O
+mild,O
+-,O
+to,O
+-,O
+moderate,O
+reactions,O
+,,O
+suggestive,O
+of,O
+hypersensitivity,O
+,,O
+that,O
+were,O
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+conservatively,O
+.,O
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+Of,O
+15,O
+patients,O
+,,O
+8,O
+(,O
+53,O
+%,O
+),O
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+IgG,O
+antibodies,O
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+r,O
+-,O
+halphaGalA,O
+;,O
+however,O
+,,O
+the,O
+antibodies,O
+were,O
+not,O
+neutralizing,O
+,,O
+as,O
+indicated,O
+by,O
+unchanged,O
+pharmacokinetic,O
+values,O
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+infusions,O
+1,O
+and,O
+5,O
+.,O
+ , 
+This,O
+study,O
+provides,O
+the,O
+basis,O
+for,O
+a,O
+phase,O
+3,O
+trial,O
+of,O
+enzyme,O
+-,O
+replacement,O
+therapy,O
+for,O
+Fabry,O
+disease,O
+.,O
+ , 
+#16086324
+Comparison,O
+of,O
+yield,O
+and,O
+genotyping,O
+performance,O
+of,O
+multiple,O
+displacement,O
+amplification,O
+and,O
+OmniPlex,O
+whole,O
+genome,O
+amplified,O
+DNA,O
+generated,O
+from,O
+multiple,O
+DNA,O
+sources,O
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+ , 
+The,O
+promise,O
+of,O
+whole,O
+genome,O
+amplification,O
+(,O
+WGA,O
+),O
+is,O
+that,O
+genomic,O
+DNA,O
+(,O
+gDNA,O
+),O
+quantity,O
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+not,O
+limit,O
+molecular,O
+genetic,O
+analyses,O
+.,O
+ , 
+Multiple,O
+displacement,O
+amplification,O
+(,O
+MDA,O
+),O
+and,O
+the,O
+OmniPlex,O
+PCR,O
+-,O
+based,O
+WGA,O
+protocols,O
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+evaluated,O
+using,O
+4,O
+and,O
+5,O
+ng,O
+of,O
+input,O
+gDNA,O
+from,O
+60,O
+gDNA,O
+samples,O
+from,O
+three,O
+tissue,O
+sources,O
+(,O
+mouthwash,O
+,,O
+buffy,O
+coat,O
+,,O
+and,O
+lymphoblast,O
+),O
+.,O
+ , 
+WGA,O
+DNA,O
+(,O
+wgaDNA,O
+),O
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+genotyping,O
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+using,O
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+from,O
+gDNA,O
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+AmpFlSTR,O
+Identifiler,O
+assay,O
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+TaqMan,O
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+Short,O
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+(,O
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+SNP,O
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+rates,O
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+reduced,O
+with,O
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+gDNA,O
+.,O
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+OmniPlex,O
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+MDA,O
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+.,O
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+Reduced,O
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+due,O
+to,O
+allelic,O
+(,O
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+),O
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+locus,O
+(,O
+OmniPlex,O
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+heterozygote,O
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+locus,O
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+,,O
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+,,O
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+%,O
+GC,O
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+(,O
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+TaqMan,O
+assay,O
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+Lymphoblast,O
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+higher,O
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+(,O
+OmniPlex,O
+),O
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+Genotyping,O
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+=,O
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+ng,O
+gDNA,O
+,,O
+e.g.,O
+,,O
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+archaeological,O
+,,O
+forensic,O
+,,O
+prenatal,O
+diagnostic,O
+,,O
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+pathology,O
+samples,O
+,,O
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+require,O
+additional,O
+genotyping,O
+validation,O
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+gDNA,O
+and/or,O
+more,O
+sophisticated,O
+analysis,O
+of,O
+genotypes,O
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+performance,O
+.,O
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+#12080485
+Mutations,O
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+genes,O
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+of,O
+a,O
+receptor,O
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+complex,O
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+identical,O
+disease,O
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+.,O
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+Polycystic,O
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+",O
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+-,O
+Hakola,O
+disease,O
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+",O
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+inherited,O
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+death,O
+during,O
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+5th,O
+decade,O
+of,O
+life,O
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+progressive,O
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+and,O
+bone,O
+cysts,O
+.,O
+ , 
+Elsewhere,O
+,,O
+we,O
+have,O
+identified,O
+PLOSL,O
+mutations,O
+in,O
+TYROBP,B-Gene
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+DAP12,I-Gene
+),I-Gene
+,,O
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+natural,O
+-,O
+killer,O
+and,O
+myeloid,O
+cells,O
+,,O
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+have,O
+identified,O
+genetic,O
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+,,O
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+some,O
+patients,O
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+no,O
+mutations,O
+in,O
+TYROBP,B-Gene
+.,I-Gene
+ , 
+Here,O
+we,O
+complete,O
+the,O
+molecular,O
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+PLOSL,O
+by,O
+identifying,O
+TREM2,B-Gene
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+second,O
+PLOSL,O
+gene,O
+.,O
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+TREM2,B-Gene
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+TYROBP,B-Gene
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+activation,O
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+the,O
+immune,O
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+macrophages,O
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+dendritic,O
+cells,O
+.,O
+ , 
+Patients,O
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+PLOSL,O
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+defects,O
+in,O
+cell,O
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+,,O
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+a,O
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+capacity,O
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+human,O
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+TYROBP,B-Gene
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+Our,O
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+TYROBP,B-Gene
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+plays,O
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+significant,O
+role,O
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+brain,O
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+bone,O
+tissue,O
+and,O
+provide,O
+an,O
+interesting,O
+example,O
+of,O
+how,O
+mutations,O
+in,O
+two,O
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+subunits,O
+of,O
+a,O
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+receptor,O
+complex,O
+result,O
+in,O
+an,O
+identical,O
+human,O
+disease,O
+phenotype,O
+.,O
+ , 
+#7581409
+Two,O
+new,O
+mutations,O
+,,O
+Q473X,B-SNP
+and,O
+N487S,B-SNP
+,,I-SNP
+in,O
+a,O
+Caucasian,O
+patient,O
+with,O
+mucopolysaccharidosis,O
+IVA,O
+(,O
+Morquio,O
+disease,O
+),O
+.,O
+ , 
+#18454449
+A,O
+meta,O
+-,O
+analysis,O
+of,O
+nonsense,O
+mutations,O
+causing,O
+human,O
+genetic,O
+disease,O
+.,O
+ , 
+Nonsense,O
+mutations,O
+account,O
+for,O
+approximately,O
+11,O
+%,O
+of,O
+all,O
+described,O
+gene,O
+lesions,O
+causing,O
+human,O
+inherited,O
+disease,O
+and,O
+approximately,O
+20,O
+%,O
+of,O
+disease,O
+-,O
+associated,O
+single,O
+-,O
+basepair,O
+substitutions,O
+affecting,O
+gene,O
+coding,O
+regions,O
+.,O
+ , 
+Pathological,O
+nonsense,O
+mutations,O
+resulting,O
+in,O
+TGA,O
+(,O
+38.5,O
+%,O
+),O
+,,O
+TAG,O
+(,O
+40.4,O
+%,O
+),O
+,,O
+and,O
+TAA,O
+(,O
+21.1,O
+%,O
+),O
+occur,O
+in,O
+different,O
+proportions,O
+to,O
+naturally,O
+occurring,O
+stop,O
+codons,O
+.,O
+ , 
+Of,O
+the,O
+23,O
+different,O
+nucleotide,O
+substitutions,O
+giving,O
+rise,O
+to,O
+nonsense,O
+mutations,O
+,,O
+the,O
+most,O
+frequent,O
+are,O
+CGA,O
+--,O
+>,O
+TGA,O
+(,O
+21,O
+%,O
+;,O
+resulting,O
+from,O
+methylation,O
+-,O
+mediated,O
+deamination,O
+),O
+and,O
+CAG,O
+--,O
+>,O
+TAG,O
+(,O
+19,O
+%,O
+),O
+.,O
+ , 
+The,O
+differing,O
+nonsense,O
+mutation,O
+frequencies,O
+are,O
+largely,O
+explicable,O
+in,O
+terms,O
+of,O
+variable,O
+nucleotide,O
+substitution,O
+rates,O
+such,O
+that,O
+it,O
+is,O
+unnecessary,O
+to,O
+invoke,O
+differential,O
+translational,O
+termination,O
+efficiency,O
+or,O
+differential,O
+codon,O
+usage,O
+.,O
+ , 
+Some,O
+genes,O
+are,O
+characterized,O
+by,O
+numerous,O
+nonsense,O
+mutations,O
+but,O
+relatively,O
+few,O
+if,O
+any,O
+missense,O
+mutations,O
+(,O
+e.g.,O
+,,O
+CHM,B-Gene
+),I-Gene
+whereas,O
+other,O
+genes,O
+exhibit,O
+many,O
+missense,O
+mutations,O
+but,O
+few,O
+if,O
+any,O
+nonsense,O
+mutations,O
+(,O
+e.g.,O
+,,O
+PSEN1,B-Gene
+),I-Gene
+.,O
+ , 
+Genes,O
+in,O
+the,O
+latter,O
+category,O
+have,O
+a,O
+tendency,O
+to,O
+encode,O
+proteins,O
+characterized,O
+by,O
+multimer,O
+formation,O
+.,O
+ , 
+Consistent,O
+with,O
+the,O
+operation,O
+of,O
+a,O
+clinical,O
+selection,O
+bias,O
+,,O
+genes,O
+exhibiting,O
+an,O
+excess,O
+of,O
+nonsense,O
+mutations,O
+are,O
+also,O
+likely,O
+to,O
+display,O
+an,O
+excess,O
+of,O
+frameshift,O
+mutations,O
+.,O
+ , 
+Tumor,O
+suppressor,O
+(,O
+TS,O
+),O
+genes,O
+exhibit,O
+a,O
+disproportionate,O
+number,O
+of,O
+nonsense,O
+mutations,O
+while,O
+most,O
+mutations,O
+in,O
+oncogenes,O
+are,O
+missense,O
+.,O
+ , 
+A,O
+total,O
+of,O
+12,O
+%,O
+of,O
+somatic,O
+nonsense,O
+mutations,O
+in,O
+TS,O
+genes,O
+were,O
+found,O
+to,O
+occur,O
+recurrently,O
+in,O
+the,O
+hypermutable,O
+CpG,O
+dinucleotide,O
+.,O
+ , 
+In,O
+a,O
+comparison,O
+of,O
+somatic,O
+and,O
+germline,O
+mutational,O
+spectra,O
+for,O
+17,O
+TS,O
+genes,O
+,,O
+approximately,O
+43,O
+%,O
+of,O
+somatic,O
+nonsense,O
+mutations,O
+had,O
+counterparts,O
+in,O
+the,O
+germline,O
+(,O
+rising,O
+to,O
+98,O
+%,O
+for,O
+CpG,O
+mutations,O
+),O
+.,O
+ , 
+Finally,O
+,,O
+the,O
+proportion,O
+of,O
+disease,O
+-,O
+causing,O
+nonsense,O
+mutations,O
+predicted,O
+to,O
+elicit,O
+nonsense,O
+-,O
+mediated,O
+mRNA,O
+decay,O
+(,O
+NMD,O
+),O
+is,O
+significantly,O
+higher,O
+(,O
+P=1.56,O
+x,O
+10(-9,O
+),O
+),O
+than,O
+among,O
+nonobserved,O
+(,O
+potential,O
+),O
+nonsense,O
+mutations,O
+,,O
+implying,O
+that,O
+nonsense,O
+mutations,O
+that,O
+elicit,O
+NMD,O
+are,O
+more,O
+likely,O
+to,O
+come,O
+to,O
+clinical,O
+attention,O
+.,O
+ , 
+#9311748
+Accurate,O
+inference,O
+of,O
+relationships,O
+in,O
+sib,O
+-,O
+pair,O
+linkage,O
+studies,O
+.,O
+ , 
+Relative,O
+-,O
+pair,O
+designs,O
+are,O
+routinely,O
+employed,O
+in,O
+linkage,O
+studies,O
+of,O
+complex,O
+genetic,O
+diseases,O
+and,O
+quantitative,O
+traits,O
+.,O
+ , 
+Valid,O
+application,O
+of,O
+these,O
+methods,O
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+correct,O
+specification,O
+of,O
+the,O
+relationships,O
+of,O
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+pairs,O
+.,O
+ , 
+For,O
+example,O
+,,O
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+a,O
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+,,O
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+full,O
+sibs,O
+actually,O
+might,O
+be,O
+MZ,O
+twins,O
+,,O
+half,O
+sibs,O
+,,O
+or,O
+unrelated,O
+.,O
+ , 
+Misclassification,O
+of,O
+half,O
+-,O
+sib,O
+pairs,O
+or,O
+unrelated,O
+individuals,O
+as,O
+full,O
+sibs,O
+can,O
+result,O
+in,O
+reduced,O
+power,O
+to,O
+detect,O
+linkage,O
+.,O
+ , 
+When,O
+other,O
+family,O
+members,O
+,,O
+such,O
+as,O
+parents,O
+or,O
+additional,O
+siblings,O
+,,O
+are,O
+available,O
+,,O
+incorrectly,O
+specified,O
+relationships,O
+usually,O
+will,O
+be,O
+detected,O
+through,O
+apparent,O
+incompatibilities,O
+with,O
+Mendelian,O
+inheritance,O
+.,O
+ , 
+Without,O
+other,O
+family,O
+members,O
+,,O
+sibling,O
+relationships,O
+can,O
+not,O
+be,O
+determined,O
+absolutely,O
+,,O
+but,O
+they,O
+still,O
+can,O
+be,O
+inferred,O
+probabilistically,O
+if,O
+sufficient,O
+genetic,O
+marker,O
+data,O
+are,O
+available,O
+.,O
+ , 
+In,O
+this,O
+paper,O
+,,O
+we,O
+describe,O
+a,O
+simple,O
+likelihood,O
+ratio,O
+method,O
+to,O
+infer,O
+the,O
+true,O
+relationship,O
+of,O
+a,O
+putative,O
+sibling,O
+pair,O
+.,O
+ , 
+We,O
+explore,O
+the,O
+number,O
+of,O
+markers,O
+required,O
+to,O
+accurately,O
+infer,O
+relationships,O
+typically,O
+encountered,O
+in,O
+a,O
+sib,O
+-,O
+pair,O
+study,O
+,,O
+as,O
+a,O
+function,O
+of,O
+marker,O
+allele,O
+frequencies,O
+,,O
+marker,O
+spacing,O
+,,O
+and,O
+genotyping,O
+error,O
+rate,O
+,,O
+and,O
+we,O
+conclude,O
+that,O
+very,O
+accurate,O
+inference,O
+of,O
+relationships,O
+can,O
+be,O
+achieved,O
+,,O
+given,O
+the,O
+marker,O
+data,O
+from,O
+even,O
+part,O
+of,O
+a,O
+genome,O
+scan,O
+.,O
+ , 
+We,O
+compare,O
+our,O
+method,O
+to,O
+related,O
+methods,O
+of,O
+relationship,O
+inference,O
+that,O
+have,O
+been,O
+suggested,O
+.,O
+ , 
+Finally,O
+,,O
+we,O
+demonstrate,O
+the,O
+value,O
+of,O
+excluding,O
+non,O
+-,O
+full,O
+sibs,O
+in,O
+a,O
+genetic,O
+linkage,O
+study,O
+of,O
+non,O
+-,O
+insulin,O
+-,O
+dependent,O
+diabetes,O
+mellitus,O
+.,O
+ , 
+#18252214
+Selection,O
+against,O
+pathogenic,O
+mtDNA,O
+mutations,O
+in,O
+a,O
+stem,O
+cell,O
+population,O
+leads,O
+to,O
+the,O
+loss,O
+of,O
+the,O
+3243A-->G,B-SNP
+mutation,O
+in,O
+blood,O
+.,O
+ , 
+The,O
+mutation,O
+3243A-->G,B-SNP
+is,O
+the,O
+most,O
+common,O
+heteroplasmic,O
+pathogenic,O
+mitochondrial,O
+DNA,O
+(,O
+mtDNA,O
+),O
+mutation,O
+in,O
+humans,O
+,,O
+but,O
+it,O
+is,O
+not,O
+understood,O
+why,O
+the,O
+proportion,O
+of,O
+this,O
+mutation,O
+decreases,O
+in,O
+blood,O
+during,O
+life,O
+.,O
+ , 
+Changing,O
+levels,O
+of,O
+mtDNA,O
+heteroplasmy,O
+are,O
+fundamentally,O
+related,O
+to,O
+the,O
+pathophysiology,O
+of,O
+the,O
+mitochondrial,O
+disease,O
+and,O
+correlate,O
+with,O
+clinical,O
+progression,O
+.,O
+ , 
+To,O
+understand,O
+this,O
+process,O
+,,O
+we,O
+simulated,O
+the,O
+segregation,O
+of,O
+mtDNA,O
+in,O
+hematopoietic,O
+stem,O
+cells,O
+and,O
+leukocyte,O
+precursors,O
+.,O
+ , 
+Our,O
+observations,O
+show,O
+that,O
+the,O
+percentage,O
+of,O
+mutant,O
+mtDNA,O
+in,O
+blood,O
+decreases,O
+exponentially,O
+over,O
+time,O
+.,O
+ , 
+This,O
+is,O
+consistent,O
+with,O
+the,O
+existence,O
+of,O
+a,O
+selective,O
+process,O
+acting,O
+at,O
+the,O
+stem,O
+cell,O
+level,O
+and,O
+explains,O
+why,O
+the,O
+level,O
+of,O
+mutant,O
+mtDNA,O
+in,O
+blood,O
+is,O
+almost,O
+invariably,O
+lower,O
+than,O
+in,O
+nondividing,O
+(,O
+postmitotic,O
+),O
+tissues,O
+such,O
+as,O
+skeletal,O
+muscle,O
+.,O
+ , 
+By,O
+using,O
+this,O
+approach,O
+,,O
+we,O
+derived,O
+a,O
+formula,O
+from,O
+human,O
+data,O
+to,O
+correct,O
+for,O
+the,O
+change,O
+in,O
+heteroplasmy,O
+over,O
+time,O
+.,O
+ , 
+A,O
+comparison,O
+of,O
+age,O
+-,O
+corrected,O
+blood,O
+heteroplasmy,O
+levels,O
+with,O
+skeletal,O
+muscle,O
+,,O
+an,O
+embryologically,O
+distinct,O
+postmitotic,O
+tissue,O
+,,O
+provides,O
+independent,O
+confirmation,O
+of,O
+the,O
+model,O
+.,O
+ , 
+These,O
+findings,O
+indicate,O
+that,O
+selection,O
+against,O
+pathogenic,O
+mtDNA,O
+mutations,O
+occurs,O
+in,O
+a,O
+stem,O
+cell,O
+population,O
+.,O
+ , 
+#15114531
+Genetic,O
+signatures,O
+of,O
+strong,O
+recent,O
+positive,O
+selection,O
+at,O
+the,O
+lactase,B-Gene
+gene,O
+.,O
+ , 
+In,O
+most,O
+human,O
+populations,O
+,,O
+the,O
+ability,O
+to,O
+digest,O
+lactose,O
+contained,O
+in,O
+milk,O
+usually,O
+disappears,O
+in,O
+childhood,O
+,,O
+but,O
+in,O
+European,O
+-,O
+derived,O
+populations,O
+,,O
+lactase,B-Gene
+activity,O
+frequently,O
+persists,O
+into,O
+adulthood,O
+(,O
+Scrimshaw,O
+and,O
+Murray,O
+1988,O
+),O
+.,O
+ , 
+It,O
+has,O
+been,O
+suggested,O
+(,O
+Cavalli,O
+-,O
+Sforza,O
+1973,O
+;,O
+Hollox,O
+et,O
+al,O
+.,O
+2001,O
+;,O
+Enattah,O
+et,O
+al,O
+.,O
+2002,O
+;,O
+ , 
+Poulter,O
+et,O
+al,O
+.,O
+2003,O
+),O
+that,O
+a,O
+selective,O
+advantage,O
+based,O
+on,O
+additional,O
+nutrition,O
+from,O
+dairy,O
+explains,O
+these,O
+genetically,O
+determined,O
+population,O
+differences,O
+(,O
+Simoons,O
+1970,O
+;,O
+Kretchmer,O
+1971,O
+;,O
+Scrimshaw,O
+and,O
+Murray,O
+1988,O
+;,O
+Enattah,O
+et,O
+al,O
+.,O
+2002,O
+),O
+,,O
+but,O
+formal,O
+population,O
+-,O
+genetics,O
+-,O
+based,O
+evidence,O
+of,O
+selection,O
+has,O
+not,O
+yet,O
+been,O
+provided,O
+.,O
+ , 
+To,O
+assess,O
+the,O
+population,O
+-,O
+genetics,O
+evidence,O
+for,O
+selection,O
+,,O
+we,O
+typed,O
+101,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+covering,O
+3.2,O
+Mb,O
+around,O
+the,O
+lactase,B-Gene
+gene,O
+.,O
+ , 
+In,O
+northern,O
+European,O
+-,O
+derived,O
+populations,O
+,,O
+two,O
+alleles,O
+that,O
+are,O
+tightly,O
+associated,O
+with,O
+lactase,O
+persistence,O
+(,O
+Enattah,O
+et,O
+al,O
+.,O
+2002,O
+),O
+uniquely,O
+mark,O
+a,O
+common,O
+(,O
+~77,O
+%,O
+),O
+haplotype,O
+that,O
+extends,O
+largely,O
+undisrupted,O
+for,O
+>,O
+1,O
+Mb,O
+.,O
+ , 
+We,O
+provide,O
+two,O
+new,O
+lines,O
+of,O
+genetic,O
+evidence,O
+that,O
+this,O
+long,O
+,,O
+common,O
+haplotype,O
+arose,O
+rapidly,O
+due,O
+to,O
+recent,O
+selection,O
+:,O
+(,O
+1,O
+),O
+by,O
+use,O
+of,O
+the,O
+traditional,O
+F(ST,O
+),O
+measure,O
+and,O
+a,O
+novel,O
+test,O
+based,O
+on,O
+p(excess,O
+),O
+,,O
+we,O
+demonstrate,O
+large,O
+frequency,O
+differences,O
+among,O
+populations,O
+for,O
+the,O
+persistence,O
+-,O
+associated,O
+markers,O
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+for,O
+flanking,O
+markers,O
+throughout,O
+the,O
+haplotype,O
+,,O
+and,O
+(,O
+2,O
+),O
+we,O
+show,O
+that,O
+the,O
+haplotype,O
+is,O
+unusually,O
+long,O
+,,O
+given,O
+its,O
+high,O
+frequency,O
+--,O
+a,O
+hallmark,O
+of,O
+recent,O
+selection,O
+.,O
+ , 
+We,O
+estimate,O
+that,O
+strong,O
+selection,O
+occurred,O
+within,O
+the,O
+past,O
+5,000,O
+-,O
+10,000,O
+years,O
+,,O
+consistent,O
+with,O
+an,O
+advantage,O
+to,O
+lactase,O
+persistence,O
+in,O
+the,O
+setting,O
+of,O
+dairy,O
+farming,O
+;,O
+the,O
+signals,O
+of,O
+selection,O
+we,O
+observe,O
+are,O
+among,O
+the,O
+strongest,O
+yet,O
+seen,O
+for,O
+any,O
+gene,O
+in,O
+the,O
+genome,O
+.,O
+ , 
+#8199597
+Sequence,O
+of,O
+the,O
+-530,O
+region,O
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+beta,B-Gene
+-,I-Gene
+globin,I-Gene
+gene,O
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+sickle,O
+cell,O
+anemia,O
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+the,O
+Arabian,O
+haplotype,O
+.,O
+ , 
+#17279550
+Comprehensive,O
+evaluation,O
+of,O
+allele,O
+frequency,O
+differences,O
+of,O
+MC1R,B-Gene
+variants,O
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+populations,O
+.,O
+ , 
+The,O
+melanocortin,B-Gene
+1,I-Gene
+receptor,I-Gene
+(,B-Gene
+MC1R,I-Gene
+),I-Gene
+,,O
+a,O
+member,O
+of,O
+the,O
+G,O
+protein,O
+-,O
+coupled,O
+receptors,O
+superfamily,O
+,,O
+mediates,O
+the,O
+response,O
+to,O
+melanocortins,O
+and,O
+is,O
+currently,O
+the,O
+best,O
+-,O
+described,O
+contributor,O
+to,O
+normal,O
+pigment,O
+variation,O
+in,O
+humans,O
+.,O
+ , 
+A,O
+remarkably,O
+large,O
+number,O
+of,O
+natural,O
+polymorphisms,O
+,,O
+or,O
+variants,O
+,,O
+of,O
+the,O
+MC1R,B-Gene
+gene,O
+have,O
+been,O
+identified,O
+in,O
+different,O
+populations,O
+.,O
+ , 
+Some,O
+of,O
+these,O
+variants,O
+have,O
+been,O
+associated,O
+with,O
+specific,O
+hair,O
+and,O
+skin,O
+color,O
+phenotypes,O
+,,O
+the,O
+presence,O
+of,O
+freckling,O
+,,O
+and,O
+melanoma,O
+and,O
+nonmelanoma,O
+skin,O
+cancer,O
+risk,O
+.,O
+ , 
+Interestingly,O
+,,O
+some,O
+MC1R,B-Gene
+variants,O
+have,O
+been,O
+associated,O
+with,O
+skin,O
+cancer,O
+beyond,O
+their,O
+effects,O
+on,O
+pigmentation,O
+.,O
+ , 
+Although,O
+the,O
+red,O
+hair,O
+color,O
+variants,O
+(,O
+RHC,O
+variants,O
+),O
+have,O
+been,O
+associated,O
+with,O
+skin,O
+cancer,O
+risk,O
+in,O
+the,O
+Celtic,O
+population,O
+,,O
+studies,O
+in,O
+darkly,O
+-,O
+pigmented,O
+Caucasian,O
+populations,O
+have,O
+demonstrated,O
+the,O
+importance,O
+of,O
+non,O
+-,O
+RHC,O
+MC1R,B-Gene
+variants,O
+on,O
+skin,O
+cancer,O
+risk,O
+as,O
+well,O
+.,O
+ , 
+We,O
+have,O
+reviewed,O
+and,O
+compared,O
+allele,O
+frequency,O
+differences,O
+of,O
+MC1R,B-Gene
+variants,O
+across,O
+geographic,O
+regions,O
+.,O
+ , 
+We,O
+observed,O
+large,O
+differences,O
+in,O
+the,O
+distribution,O
+of,O
+variants,O
+across,O
+populations,O
+,,O
+with,O
+a,O
+prominent,O
+difference,O
+between,O
+lightly,O
+and,O
+darkly,O
+-,O
+pigmented,O
+individuals,O
+.,O
+ , 
+Moreover,O
+,,O
+among,O
+Caucasian,O
+groups,O
+,,O
+there,O
+were,O
+seven,O
+variants,O
+(,B-SNP
+p.,I-SNP
+V60L,I-SNP
+,,I-SNP
+p.,B-SNP
+V92,I-SNP
+M,I-SNP
+,,I-SNP
+p.,B-SNP
+D84E,I-SNP
+,,I-SNP
+p.,B-SNP
+R151C,I-SNP
+,,I-SNP
+p.,B-SNP
+R160W,I-SNP
+,,I-SNP
+p.,B-SNP
+R163Q,I-SNP
+,,I-SNP
+and,O
+p.,B-SNP
+D294H,I-SNP
+),I-SNP
+with,O
+significantly,O
+different,O
+allele,O
+frequencies,O
+.,O
+ , 
+Exploring,O
+differences,O
+in,O
+allele,O
+frequencies,O
+of,O
+MC1R,B-Gene
+variants,O
+across,O
+populations,O
+with,O
+varying,O
+pigmentation,O
+and,O
+differing,O
+skin,O
+cancer,O
+risk,O
+may,O
+improve,O
+our,O
+understanding,O
+of,O
+the,O
+complex,O
+relationship,O
+between,O
+MC1R,B-Gene
+,,I-Gene
+pigmentation,O
+,,O
+and,O
+carcinogenesis,O
+.,O
+ , 
+#21549338
+A,O
+missense,O
+mutation,O
+in,O
+PRPF6,B-Gene
+causes,O
+impairment,O
+of,O
+pre,O
+-,O
+mRNA,O
+splicing,O
+and,O
+autosomal,O
+-,O
+dominant,O
+retinitis,O
+pigmentosa,O
+.,O
+ , 
+Retinitis,O
+pigmentosa,O
+(,O
+RP,O
+),O
+is,O
+an,O
+inherited,O
+form,O
+of,O
+retinal,O
+degeneration,O
+that,O
+leads,O
+to,O
+progressive,O
+visual,O
+-,O
+field,O
+constriction,O
+and,O
+blindness,O
+.,O
+ , 
+Although,O
+the,O
+disease,O
+manifests,O
+only,O
+in,O
+the,O
+retina,O
+,,O
+mutations,O
+in,O
+ubiquitously,O
+expressed,O
+genes,O
+associated,O
+with,O
+the,O
+tri,O
+-,O
+snRNP,O
+complex,O
+of,O
+the,O
+spliceosome,O
+have,O
+been,O
+identified,O
+in,O
+patients,O
+with,O
+dominantly,O
+inherited,O
+RP,O
+.,O
+ , 
+We,O
+screened,O
+for,O
+mutations,O
+in,O
+PRPF6,B-Gene
+(,O
+NM_012469.3,O
+),O
+,,O
+a,O
+gene,O
+on,O
+chromosome,O
+20q13.33,O
+encoding,O
+an,O
+essential,O
+protein,O
+for,O
+tri,O
+-,O
+snRNP,O
+assembly,O
+and,O
+stability,O
+,,O
+in,O
+188,O
+unrelated,O
+patients,O
+with,O
+autosomal,O
+-,O
+dominant,O
+RP,O
+and,O
+identified,O
+a,O
+missense,O
+mutation,O
+,,O
+c.2185C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Arg729Trp,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+change,O
+affected,O
+a,O
+residue,O
+that,O
+is,O
+conserved,O
+from,O
+humans,O
+to,O
+yeast,O
+and,O
+cosegregated,O
+with,O
+the,O
+disease,O
+in,O
+the,O
+family,O
+in,O
+which,O
+it,O
+was,O
+identified,O
+.,O
+ , 
+Lymphoblasts,O
+derived,O
+from,O
+patients,O
+with,O
+this,O
+mutation,O
+showed,O
+abnormal,O
+localization,O
+of,O
+endogenous,O
+PRPF6,B-Gene
+within,O
+the,O
+nucleus,O
+.,O
+ , 
+Specifically,O
+,,O
+this,O
+protein,O
+accumulated,O
+in,O
+the,O
+Cajal,O
+bodies,O
+,,O
+indicating,O
+a,O
+possible,O
+impairment,O
+in,O
+the,O
+tri,O
+-,O
+snRNP,O
+assembly,O
+or,O
+recycling,O
+.,O
+ , 
+Expression,O
+of,O
+GFP,O
+-,O
+tagged,O
+PRPF6,B-Gene
+in,O
+HeLa,O
+cells,O
+showed,O
+that,O
+this,O
+phenomenon,O
+depended,O
+exclusively,O
+on,O
+the,O
+mutated,O
+form,O
+of,O
+the,O
+protein,O
+.,O
+ , 
+Furthermore,O
+,,O
+analysis,O
+of,O
+endogenous,O
+transcripts,O
+in,O
+cells,O
+from,O
+patients,O
+revealed,O
+intron,O
+retention,O
+for,O
+pre,O
+-,O
+mRNA,O
+bearing,O
+specific,O
+splicing,O
+signals,O
+,,O
+according,O
+to,O
+the,O
+same,O
+pattern,O
+displayed,O
+by,O
+lymphoblasts,O
+with,O
+mutations,O
+in,O
+other,O
+PRPF,O
+genes,O
+.,O
+ , 
+Our,O
+results,O
+identify,O
+PRPF6,B-Gene
+as,O
+the,O
+sixth,O
+gene,O
+involved,O
+in,O
+pre,O
+-,O
+mRNA,O
+splicing,O
+and,O
+dominant,O
+RP,O
+,,O
+corroborating,O
+the,O
+hypothesis,O
+that,O
+deficiencies,O
+in,O
+the,O
+spliceosome,O
+play,O
+an,O
+important,O
+role,O
+in,O
+the,O
+molecular,O
+pathology,O
+of,O
+this,O
+disease,O
+.,O
+ , 
+#8533774
+Discordant,O
+patterns,O
+of,O
+linkage,O
+disequilibrium,O
+of,O
+the,O
+peptide,O
+-,O
+transporter,O
+loci,O
+within,O
+the,O
+HLA,O
+class,O
+II,O
+region,O
+.,O
+ , 
+Disequilibrium,O
+between,O
+genetic,O
+markers,O
+is,O
+expected,O
+to,O
+decline,O
+monotonically,O
+with,O
+recombinational,O
+map,O
+distance,O
+.,O
+ , 
+We,O
+present,O
+evidence,O
+from,O
+the,O
+HLA,O
+class,O
+II,O
+region,O
+that,O
+seems,O
+to,O
+violate,O
+this,O
+principle,O
+.,O
+ , 
+Pairwise,O
+disequilibrium,O
+values,O
+were,O
+calculated,O
+from,O
+six,O
+loci,O
+ranging,O
+in,O
+physical,O
+separation,O
+from,O
+15,O
+kb,O
+to,O
+550,O
+kb,O
+.,O
+ , 
+The,O
+histocompatibility,O
+loci,O
+DRB1,B-Gene
+,,I-Gene
+DQA1,B-Gene
+,,I-Gene
+and,O
+DQB1,B-Gene
+,,I-Gene
+located,O
+on,O
+the,O
+distal,O
+end,O
+of,O
+the,O
+class,O
+II,O
+region,O
+,,O
+behave,O
+as,O
+a,O
+single,O
+evolutionary,O
+unit,O
+within,O
+which,O
+extremely,O
+high,O
+linkage,O
+disequilibrium,O
+exists,O
+.,O
+ , 
+Lower,O
+but,O
+still,O
+significant,O
+levels,O
+of,O
+disequilibrium,O
+are,O
+present,O
+between,O
+these,O
+loci,O
+and,O
+DPB1,B-Gene
+,,I-Gene
+located,O
+at,O
+the,O
+proximal,O
+edge,O
+of,O
+the,O
+HLA,O
+complex,O
+.,O
+ , 
+The,O
+peptide,O
+-,O
+transporter,O
+loci,O
+TAP1,B-Gene
+and,O
+TAP2,B-Gene
+,,I-Gene
+located,O
+in,O
+the,O
+intervening,O
+region,O
+,,O
+reveal,O
+no,O
+disequilibrium,O
+with,O
+each,O
+other,O
+and,O
+low,O
+or,O
+negligible,O
+disequilibrium,O
+with,O
+the,O
+flanking,O
+loci,O
+.,O
+ , 
+The,O
+action,O
+of,O
+two,O
+genetic,O
+process,O
+is,O
+required,O
+to,O
+account,O
+for,O
+this,O
+phenomenon,O
+:,O
+a,O
+recombinational,O
+hotspot,O
+operating,O
+between,O
+TAP1,B-Gene
+and,O
+TAP2,B-Gene
+,,I-Gene
+to,O
+eliminate,O
+disequilibrium,O
+between,O
+these,O
+loci,O
+,,O
+and,O
+at,O
+the,O
+same,O
+time,O
+selection,O
+operating,O
+on,O
+particular,O
+combinations,O
+of,O
+alleles,O
+across,O
+the,O
+DR,O
+-,O
+DP,O
+region,O
+,,O
+to,O
+create,O
+disequilibrium,O
+in,O
+the,O
+favored,O
+haplotypes,O
+.,O
+ , 
+The,O
+forces,O
+producing,O
+the,O
+patterns,O
+of,O
+disequilibrium,O
+observed,O
+here,O
+have,O
+implications,O
+for,O
+the,O
+mapping,O
+of,O
+train,O
+loci,O
+and,O
+disease,O
+genes,O
+:,O
+markers,O
+of,O
+TAP1,B-Gene
+,,I-Gene
+for,O
+example,O
+,,O
+would,O
+give,O
+a,O
+false,O
+impression,O
+as,O
+to,O
+the,O
+influence,O
+of,O
+DPB1,B-Gene
+on,O
+a,O
+trait,O
+known,O
+to,O
+be,O
+associated,O
+with,O
+DQB1,B-Gene
+.,I-Gene
+ , 
+#22405084
+2011,O
+William,O
+Allan,O
+Award,O
+:,O
+development,O
+and,O
+evolution,O
+.,O
+ , 
+#9326328
+Identification,O
+of,O
+a,O
+locus,O
+for,O
+progressive,O
+familial,O
+intrahepatic,O
+cholestasis,O
+PFIC2,B-Gene
+on,O
+chromosome,O
+2q24,O
+.,O
+ , 
+Progressive,O
+familial,O
+intrahepatic,O
+cholestasis,O
+(,O
+PFIC,O
+;,O
+OMIM,O
+211600,O
+),O
+is,O
+the,O
+second,O
+most,O
+common,O
+familial,O
+cholestatic,O
+syndrome,O
+presenting,O
+in,O
+infancy,O
+.,O
+ , 
+A,O
+locus,O
+has,O
+previously,O
+been,O
+mapped,O
+to,O
+chromosome,O
+18q21,O
+-,O
+22,O
+in,O
+the,O
+original,O
+Byler,O
+pedigree,O
+.,O
+ , 
+This,O
+chromosomal,O
+region,O
+also,O
+harbors,O
+the,O
+locus,O
+for,O
+benign,O
+recurrent,O
+intrahepatic,O
+cholestasis,O
+(,O
+BRIC,O
+),O
+a,O
+related,O
+phenotype,O
+.,O
+ , 
+Linkage,O
+analysis,O
+in,O
+six,O
+consanguineous,O
+PFIC,B-Gene
+pedigrees,O
+from,O
+the,O
+Middle,O
+East,O
+has,O
+previously,O
+excluded,O
+linkage,O
+to,O
+chromosome,O
+18q21,O
+-,O
+22,O
+,,O
+indicating,O
+the,O
+existence,O
+of,O
+locus,O
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+within,O
+the,O
+PFIC,B-Gene
+phenotype,O
+.,O
+ , 
+By,O
+use,O
+of,O
+homozygosity,O
+mapping,O
+and,O
+a,O
+genome,O
+scan,O
+in,O
+these,O
+pedigrees,O
+,,O
+a,O
+locus,O
+designated,O
+",B-Gene
+PFIC2,I-Gene
+",I-Gene
+has,O
+been,O
+mapped,O
+to,O
+chromosome,O
+2q24,O
+.,O
+ , 
+A,O
+maximum,O
+LOD,O
+score,O
+of,O
+8.5,O
+was,O
+obtained,O
+in,O
+the,O
+interval,O
+between,O
+marker,O
+loci,O
+D2S306,O
+and,O
+D2S124,O
+,,O
+with,O
+all,O
+families,O
+linked,O
+.,O
+ , 
+#19896111
+Common,O
+variants,O
+in,O
+the,O
+trichohyalin,O
+gene,O
+are,O
+associated,O
+with,O
+straight,O
+hair,O
+in,O
+Europeans,O
+.,O
+ , 
+Hair,O
+morphology,O
+is,O
+highly,O
+differentiated,O
+between,O
+populations,O
+and,O
+among,O
+people,O
+of,O
+European,O
+ancestry,O
+.,O
+ , 
+Whereas,O
+hair,O
+morphology,O
+in,O
+East,O
+Asian,O
+populations,O
+has,O
+been,O
+studied,O
+extensively,O
+,,O
+relatively,O
+little,O
+is,O
+known,O
+about,O
+the,O
+genetics,O
+of,O
+this,O
+trait,O
+in,O
+Europeans,O
+.,O
+ , 
+We,O
+performed,O
+a,O
+genome,O
+-,O
+wide,O
+association,O
+scan,O
+for,O
+hair,O
+morphology,O
+(,O
+straight,O
+,,O
+wavy,O
+,,O
+curly,O
+),O
+in,O
+three,O
+Australian,O
+samples,O
+of,O
+European,O
+descent,O
+.,O
+ , 
+All,O
+three,O
+samples,O
+showed,O
+evidence,O
+of,O
+association,O
+implicating,O
+the,O
+Trichohyalin,B-Gene
+gene,O
+(,B-Gene
+TCHH,I-Gene
+),I-Gene
+,,O
+which,O
+is,O
+expressed,O
+in,O
+the,O
+developing,O
+inner,O
+root,O
+sheath,O
+of,O
+the,O
+hair,O
+follicle,O
+,,O
+and,O
+explaining,O
+approximately,O
+6,O
+%,O
+of,O
+variance,O
+(,O
+p=1.5x10(-31,O
+),O
+),O
+.,O
+ , 
+These,O
+variants,O
+are,O
+at,O
+their,O
+highest,O
+frequency,O
+in,O
+Northern,O
+Europeans,O
+,,O
+paralleling,O
+the,O
+distribution,O
+of,O
+the,O
+straight,O
+-,O
+hair,O
+EDAR,O
+variant,O
+in,O
+Asian,O
+populations,O
+.,O
+ , 
+#20471002
+Pooled,O
+association,O
+tests,O
+for,O
+rare,O
+variants,O
+in,O
+exon,O
+-,O
+resequencing,O
+studies,O
+.,O
+ , 
+Deep,O
+sequencing,O
+will,O
+soon,O
+generate,O
+comprehensive,O
+sequence,O
+information,O
+in,O
+large,O
+disease,O
+samples,O
+.,O
+ , 
+Although,O
+the,O
+power,O
+to,O
+detect,O
+association,O
+with,O
+an,O
+individual,O
+rare,O
+variant,O
+is,O
+limited,O
+,,O
+pooling,O
+variants,O
+by,O
+gene,O
+or,O
+pathway,O
+into,O
+a,O
+composite,O
+test,O
+provides,O
+an,O
+alternative,O
+strategy,O
+for,O
+identifying,O
+susceptibility,O
+genes,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+statistical,O
+method,O
+for,O
+detecting,O
+association,O
+of,O
+multiple,O
+rare,O
+variants,O
+in,O
+protein,O
+-,O
+coding,O
+genes,O
+with,O
+a,O
+quantitative,O
+or,O
+dichotomous,O
+trait,O
+.,O
+ , 
+The,O
+approach,O
+is,O
+based,O
+on,O
+the,O
+regression,O
+of,O
+phenotypic,O
+values,O
+on,O
+individuals,O
+',O
+genotype,O
+scores,O
+subject,O
+to,O
+a,O
+variable,O
+allele,O
+-,O
+frequency,O
+threshold,O
+,,O
+incorporating,O
+computational,O
+predictions,O
+of,O
+the,O
+functional,O
+effects,O
+of,O
+missense,O
+variants,O
+.,O
+ , 
+Statistical,O
+significance,O
+is,O
+assessed,O
+by,O
+permutation,O
+testing,O
+with,O
+variable,O
+thresholds,O
+.,O
+ , 
+We,O
+used,O
+a,O
+rigorous,O
+population,O
+-,O
+genetics,O
+simulation,O
+framework,O
+to,O
+evaluate,O
+the,O
+power,O
+of,O
+the,O
+method,O
+,,O
+and,O
+we,O
+applied,O
+the,O
+method,O
+to,O
+empirical,O
+sequencing,O
+data,O
+from,O
+three,O
+disease,O
+studies,O
+.,O
+ , 
+#10712193
+James,O
+V.,O
+Neel,O
+,,O
+M.D.,O
+,,O
+Ph.D.,O
+(,O
+March,O
+22,O
+,,O
+1915,O
+-,O
+January,O
+31,O
+,,O
+2000,O
+):,O
+founder,O
+effect,O
+.,O
+ , 
+#12442272
+D90A,B-SNP
+-,B-Gene
+SOD1,I-Gene
+mediated,O
+amyotrophic,O
+lateral,O
+sclerosis,O
+:,O
+a,O
+single,O
+founder,O
+for,O
+all,O
+cases,O
+with,O
+evidence,O
+for,O
+a,O
+Cis,O
+-,O
+acting,O
+disease,O
+modifier,O
+in,O
+the,O
+recessive,O
+haplotype,O
+.,O
+ , 
+More,O
+than,O
+100,O
+different,O
+heterozygous,O
+mutations,O
+in,O
+copper,O
+/,O
+zinc,O
+superoxide,B-Gene
+dismutase,I-Gene
+(,B-Gene
+SOD1,I-Gene
+),I-Gene
+have,O
+been,O
+found,O
+in,O
+patients,O
+with,O
+amyotrophic,O
+lateral,O
+sclerosis,O
+(,O
+ALS,O
+),O
+,,O
+a,O
+fatal,O
+neurodegenerative,O
+disease,O
+.,O
+ , 
+Uniquely,O
+,,O
+D90A,B-SNP
+-,B-Gene
+SOD1,I-Gene
+has,O
+been,O
+identified,O
+in,O
+recessive,O
+,,O
+dominant,O
+and,O
+apparently,O
+sporadic,O
+pedigrees,O
+.,O
+ , 
+The,O
+phenotype,O
+of,O
+homozygotes,O
+is,O
+stereotyped,O
+with,O
+an,O
+extended,O
+survival,O
+,,O
+whereas,O
+that,O
+of,O
+affected,O
+heterozygotes,O
+varies,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+D90A,B-SNP
+-,B-Gene
+SOD1,I-Gene
+is,O
+50,O
+times,O
+higher,O
+in,O
+Scandinavia,O
+(,O
+2.5,O
+%,O
+),O
+than,O
+elsewhere,O
+,,O
+though,O
+ALS,O
+prevalence,O
+is,O
+not,O
+raised,O
+there,O
+.,O
+ , 
+Our,O
+earlier,O
+study,O
+indicated,O
+separate,O
+founders,O
+for,O
+recessive,O
+and,O
+dominant,O
+/,O
+sporadic,O
+ALS,O
+and,O
+we,O
+proposed,O
+a,O
+disease,O
+-,O
+modifying,O
+factor,O
+linked,O
+to,O
+the,O
+recessive,O
+mutation,O
+.,O
+ , 
+Here,O
+we,O
+have,O
+doubled,O
+our,O
+sample,O
+set,O
+and,O
+employed,O
+novel,O
+markers,O
+to,O
+characterise,O
+the,O
+mutation,O
+'s,O
+origin,O
+and,O
+localise,O
+any,O
+modifying,O
+factor,O
+.,O
+ , 
+Linkage,O
+disequilibrium,O
+analysis,O
+indicates,O
+that,O
+D90A,B-SNP
+homozygotes,O
+and,O
+heterozygotes,O
+share,O
+a,O
+rare,O
+haplotype,O
+and,O
+are,O
+all,O
+descended,O
+from,O
+a,O
+single,O
+ancient,O
+founder,O
+(,O
+alpha,O
+0.974,O
+),O
+ , 
+c.895,O
+generations,O
+ago,O
+.,O
+ , 
+Homozygotes,O
+arose,O
+subsequently,O
+only,O
+c.63,O
+generations,O
+ago,O
+(,O
+alpha,O
+0.878,O
+),O
+.,O
+ , 
+Recombination,O
+has,O
+reduced,O
+the,O
+region,O
+shared,O
+by,O
+recessive,O
+kindreds,O
+to,O
+97,O
+-,O
+265,O
+kb,O
+around,O
+SOD1,B-Gene
+,,I-Gene
+excluding,O
+all,O
+neighbouring,O
+genes,O
+.,O
+ , 
+We,O
+propose,O
+that,O
+a,O
+cis,O
+-,O
+acting,O
+regulatory,O
+polymorphism,O
+has,O
+arisen,O
+close,O
+to,O
+D90A,B-SNP
+-,B-Gene
+SOD1,I-Gene
+in,O
+the,O
+recessive,O
+founder,O
+,,O
+which,O
+decreases,O
+ALS,O
+susceptibility,O
+in,O
+heterozygotes,O
+and,O
+slows,O
+disease,O
+progression,O
+.,O
+ , 
+#12872253
+Mutation,O
+screening,O
+of,O
+the,O
+N,B-Gene
+-,I-Gene
+myc,I-Gene
+downstream,I-Gene
+-,I-Gene
+regulated,I-Gene
+gene,I-Gene
+1,I-Gene
+(,B-Gene
+NDRG1,I-Gene
+),I-Gene
+in,O
+patients,O
+with,O
+Charcot,O
+-,O
+Marie,O
+-,O
+Tooth,O
+Disease,O
+.,O
+ , 
+In,O
+a,O
+previous,O
+study,O
+,,O
+we,O
+have,O
+shown,O
+that,O
+N,B-Gene
+-,I-Gene
+myc,I-Gene
+downstream,I-Gene
+-,I-Gene
+regulated,I-Gene
+gene,I-Gene
+1,I-Gene
+(,B-Gene
+NDRG1,I-Gene
+),I-Gene
+,,O
+classified,O
+in,O
+databases,O
+as,O
+a,O
+tumor,O
+suppressor,O
+and,O
+heavy,O
+metal,O
+-,O
+response,O
+protein,O
+,,O
+is,O
+mutated,O
+in,O
+hereditary,O
+motor,O
+and,O
+sensory,O
+neuropathy,O
+Lom,O
+(,O
+HMSNL,O
+),O
+,,O
+a,O
+severe,O
+autosomal,O
+recessive,O
+form,O
+of,O
+Charcot,O
+-,O
+Marie,O
+-,O
+Tooth,O
+(,O
+CMT,O
+),O
+disease,O
+.,O
+ , 
+The,O
+private,O
+founder,O
+mutation,O
+R148X,B-SNP
+,,I-SNP
+causing,O
+HMSNL,O
+in,O
+patients,O
+of,O
+Romani,O
+ethnicity,O
+,,O
+has,O
+so,O
+far,O
+remained,O
+the,O
+only,O
+molecular,O
+defect,O
+linking,O
+NDRG1,B-Gene
+to,O
+a,O
+specific,O
+disease,O
+phenotype,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+the,O
+first,O
+study,O
+aiming,O
+to,O
+assess,O
+the,O
+overall,O
+contribution,O
+of,O
+this,O
+gene,O
+to,O
+the,O
+pathogenesis,O
+of,O
+peripheral,O
+neuropathies,O
+,,O
+in,O
+cases,O
+where,O
+the,O
+most,O
+common,O
+causes,O
+of,O
+CMT,O
+disease,O
+have,O
+been,O
+excluded,O
+.,O
+ , 
+Sequence,O
+analysis,O
+of,O
+NDRG1,B-Gene
+in,O
+104,O
+CMT,O
+patients,O
+of,O
+diverse,O
+ethnicity,O
+identified,O
+one,O
+novel,O
+disease,O
+-,O
+causing,O
+mutation,O
+,,O
+IVS8,B-SNP
+-,I-SNP
+1G,I-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+g.2290787G,I-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
+,,O
+which,O
+affects,O
+the,O
+splice,O
+-,O
+acceptor,O
+site,O
+of,O
+IVS8,O
+and,O
+results,O
+in,O
+the,O
+skipping,O
+of,O
+exon,O
+9,O
+.,O
+ , 
+The,O
+phenotype,O
+of,O
+the,O
+IVS8,B-SNP
+-,I-SNP
+1G,I-SNP
+>,I-SNP
+A,I-SNP
+homozygote,O
+was,O
+very,O
+closely,O
+related,O
+to,O
+that,O
+of,O
+HMSNL,O
+patients,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+we,O
+have,O
+detected,O
+homozygosity,O
+for,O
+the,O
+known,O
+R148X,B-SNP
+mutation,O
+in,O
+two,O
+affected,O
+individuals,O
+.,O
+ , 
+Mutations,O
+in,O
+NDRG1,B-Gene
+thus,O
+accounted,O
+for,O
+2.88,O
+%,O
+of,O
+our,O
+overall,O
+group,O
+of,O
+patients,O
+,,O
+and,O
+for,O
+4.68,O
+%,O
+of,O
+cases,O
+with,O
+demyelinating,O
+neuropathies,O
+.,O
+ , 
+No,O
+other,O
+variants,O
+were,O
+identified,O
+in,O
+the,O
+coding,O
+sequence,O
+,,O
+whereas,O
+12,O
+single,O
+nucleotide,O
+polymorphisms,O
+were,O
+observed,O
+in,O
+the,O
+introns,O
+.,O
+ , 
+Hum,O
+Mutat,O
+22:129,O
+-,O
+135,O
+,,O
+2003,O
+.,O
+ , 
+#22331697
+Microarray,O
+-,O
+based,O
+copy,O
+number,O
+analysis,O
+of,O
+neurofibromatosis,O
+type-1,O
+(,O
+NF1)-associated,O
+malignant,O
+peripheral,O
+nerve,O
+sheath,O
+tumors,O
+reveals,O
+a,O
+role,O
+for,O
+Rho,O
+-,O
+GTPase,O
+pathway,O
+genes,O
+in,O
+NF1,O
+tumorigenesis,O
+.,O
+ , 
+Neurofibromatosis,O
+type-1,O
+(,O
+NF1,O
+),O
+is,O
+associated,O
+with,O
+the,O
+growth,O
+of,O
+benign,O
+and,O
+malignant,O
+tumors,O
+.,O
+ , 
+Approximately,O
+15,O
+%,O
+of,O
+NF1,O
+patients,O
+develop,O
+malignant,O
+peripheral,O
+nerve,O
+sheath,O
+tumors,O
+(,O
+MPNSTs,O
+),O
+,,O
+underlining,O
+the,O
+need,O
+to,O
+identify,O
+specific,O
+diagnostic,O
+/,O
+prognostic,O
+biomarkers,O
+associated,O
+with,O
+MPNST,O
+development,O
+.,O
+ , 
+The,O
+Affymetrix,O
+Genome,O
+-,O
+Wide,O
+Human,O
+single,O
+-,O
+nucleotide,O
+polymorphism,O
+(,O
+SNP,O
+),O
+Array,O
+6.0,O
+was,O
+used,O
+to,O
+perform,O
+SNP,O
+genotyping,O
+and,O
+copy,O
+number,O
+alteration,O
+(,O
+CNA,O
+),O
+,,O
+loss,O
+-,O
+of,O
+-,O
+heterozygosity,O
+(,O
+LOH,O
+),O
+,,O
+and,O
+copy,O
+number,O
+neutral,O
+-,O
+LOH,O
+(,O
+CNN,O
+-,O
+LOH,O
+),O
+analyses,O
+of,O
+DNA,O
+isolated,O
+from,O
+15,O
+MPNSTs,O
+,,O
+five,O
+benign,O
+plexiform,O
+neurofibromas,O
+(,O
+PNFs,O
+),O
+,,O
+and,O
+patient,O
+-,O
+matched,O
+lymphocyte,O
+DNAs,O
+.,O
+ , 
+MPNSTs,O
+exhibited,O
+high,O
+-,O
+level,O
+CNN,O
+-,O
+LOH,O
+,,O
+with,O
+recurrent,O
+changes,O
+occurring,O
+in,O
+MPNSTs,O
+but,O
+not,O
+PNFs,O
+.,O
+ , 
+CNN,O
+-,O
+LOH,O
+was,O
+evident,O
+in,O
+MPNSTs,O
+but,O
+occurred,O
+less,O
+frequently,O
+than,O
+genomic,O
+deletions,O
+.,O
+ , 
+CNAs,O
+involving,O
+the,O
+ITGB8,O
+,,O
+PDGFA,O
+,,O
+Ras,O
+-,O
+related,O
+C3,O
+botulinum,O
+toxin,O
+substrate,O
+1,O
+(,B-Gene
+RAC1,I-Gene
+),I-Gene
+(,O
+7p21,O
+-,O
+p22,O
+),O
+,,O
+PDGFRL,B-Gene
+(,O
+8p22,O
+-,O
+p21.3,O
+),O
+,,O
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+matrix,B-Gene
+metallopeptidase,I-Gene
+12,I-Gene
+(,B-Gene
+MMP12,I-Gene
+),I-Gene
+(,O
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+specific,O
+to,O
+MPNSTs,O
+.,O
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+Pathway,O
+analysis,O
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+the,O
+MPNST,O
+-,O
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+amplification,O
+of,O
+seven,O
+Rho,O
+-,O
+GTPase,O
+pathway,O
+genes,O
+and,O
+several,O
+cytoskeletal,O
+remodeling,O
+/,O
+cell,O
+adhesion,O
+genes,O
+.,O
+ , 
+In,O
+knockdown,O
+experiments,O
+employing,O
+short,O
+-,O
+hairpin,O
+RAC1,B-Gene
+,,I-Gene
+ROCK2,B-Gene
+,,I-Gene
+PTK2,B-Gene
+,,I-Gene
+and,O
+LIMK1,B-Gene
+RNAs,O
+to,O
+transfect,O
+both,O
+control,O
+and,O
+MPNST,O
+-,O
+derived,O
+cell,O
+lines,O
+,,O
+cell,O
+adhesion,O
+was,O
+significantly,O
+increased,O
+in,O
+the,O
+MPNST,O
+cell,O
+lines,O
+,,O
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+wound,O
+healing,O
+,,O
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+,,O
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+reduced,O
+,,O
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+with,O
+a,O
+role,O
+for,O
+these,O
+Rho,O
+-,O
+GTPase,O
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+genes,O
+in,O
+MPNST,O
+development,O
+and,O
+metastasis,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+new,O
+targets,O
+for,O
+therapeutic,O
+intervention,O
+in,O
+relation,O
+to,O
+MPNSTs,O
+.,O
+ , 
+#15937921
+Niemann,O
+-,O
+Pick,O
+type,O
+C,O
+disease,O
+:,O
+subcellular,O
+location,O
+and,O
+functional,O
+characterization,O
+of,O
+NPC2,B-Gene
+proteins,O
+with,O
+naturally,O
+occurring,O
+missense,O
+mutations,O
+.,O
+ , 
+Niemann,O
+-,O
+Pick,O
+disease,O
+type,O
+C,O
+(,O
+NPC,O
+),O
+,,O
+a,O
+severe,O
+neurovisceral,O
+lysosomal,O
+disorder,O
+,,O
+is,O
+due,O
+to,O
+mutations,O
+on,O
+the,O
+NPC1,B-Gene
+gene,O
+or,O
+,,O
+in,O
+a,O
+minority,O
+of,O
+families,O
+,,O
+the,O
+NPC2,B-Gene
+gene,O
+.,O
+ , 
+Few,O
+investigations,O
+have,O
+been,O
+devoted,O
+to,O
+the,O
+NPC2,B-Gene
+protein,O
+,,O
+for,O
+which,O
+only,O
+13,O
+different,O
+disease,O
+-,O
+causing,O
+mutations,O
+(,O
+including,O
+three,O
+novel,O
+ones,O
+in,O
+this,O
+report,O
+),O
+have,O
+been,O
+described,O
+.,O
+ , 
+Among,O
+the,O
+currently,O
+known,O
+NPC2,B-Gene
+mutant,O
+alleles,O
+,,O
+six,O
+resulted,O
+in,O
+a,O
+premature,O
+stop,O
+codon,O
+.,O
+ , 
+Only,O
+five,O
+missense,O
+mutations,O
+,,O
+c.115G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+V39,I-SNP
+M,I-SNP
+),I-SNP
+,,O
+c.140G,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+C47F,I-SNP
+),I-SNP
+,,O
+c.199T,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+S67P,I-SNP
+),I-SNP
+,,O
+c.278G,B-SNP
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+T,I-SNP
+(,B-SNP
+p.,I-SNP
+C93F,I-SNP
+),I-SNP
+,,O
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+(,O
+this,O
+report,O
+),O
+c.295T,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+C99R,I-SNP
+),I-SNP
+were,O
+identified,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+we,O
+generated,O
+cDNA,O
+constructs,O
+harboring,O
+each,O
+of,O
+these,O
+missense,O
+mutations,O
+and,O
+,,O
+upon,O
+overexpression,O
+in,O
+human,O
+fibroblasts,O
+with,O
+a,O
+nonsense,O
+NPC2,B-Gene
+mutation,O
+,,O
+characterized,O
+the,O
+mutated,O
+proteins,O
+by,O
+immunoblotting,O
+,,O
+immunocytofluorescence,O
+microscopy,O
+,,O
+and,O
+complementation,O
+.,O
+ , 
+Mutation,O
+p.,B-SNP
+V39,I-SNP
+M,I-SNP
+,,I-SNP
+described,O
+in,O
+the,O
+homozygous,O
+state,O
+in,O
+two,O
+patients,O
+with,O
+an,O
+adult,O
+-,O
+onset,O
+neurological,O
+disease,O
+,,O
+resulted,O
+in,O
+the,O
+synthesis,O
+of,O
+apparently,O
+functional,O
+recombinant,O
+proteins,O
+correctly,O
+targeted,O
+to,O
+lysosomes,O
+.,O
+ , 
+Although,O
+a,O
+mild,O
+functional,O
+impact,O
+could,O
+possibly,O
+be,O
+overlooked,O
+in,O
+our,O
+overexpression,O
+system,O
+,,O
+comparative,O
+studies,O
+with,O
+NPC1,O
+mutants,O
+indicated,O
+that,O
+mild,O
+mutations,O
+might,O
+not,O
+necessarily,O
+affect,O
+localization,O
+of,O
+the,O
+protein,O
+or,O
+its,O
+quantity,O
+in,O
+the,O
+native,O
+state,O
+.,O
+ , 
+Conversely,O
+,,O
+mutations,O
+p.,B-SNP
+C47F,I-SNP
+,,I-SNP
+p.,B-SNP
+C93R,I-SNP
+,,I-SNP
+p.,B-SNP
+C99R,I-SNP
+ , 
+but,O
+also,O
+,,O
+less,O
+predictably,O
+,,O
+p.,B-SNP
+S67P,I-SNP
+,,I-SNP
+led,O
+to,O
+the,O
+synthesis,O
+of,O
+misfolded,O
+recombinant,O
+proteins,O
+that,O
+colocalized,O
+with,O
+an,O
+endoplasmic,O
+reticulum,O
+marker,O
+.,O
+ , 
+The,O
+four,O
+latter,O
+proteins,O
+were,O
+normally,O
+secreted,O
+but,O
+were,O
+unable,O
+to,O
+correct,O
+cholesterol,O
+storage,O
+in,O
+NPC2(-/-,B-Gene
+),O
+cells,O
+.,O
+ , 
+Functional,O
+characterization,O
+of,O
+the,O
+mutant,O
+proteins,O
+showed,O
+an,O
+excellent,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+in,O
+the,O
+three,O
+cases,O
+for,O
+whom,O
+a,O
+clinical,O
+history,O
+was,O
+available,O
+.,O
+ , 
+#7951257
+Detecting,O
+prion,O
+protein,O
+gene,O
+mutations,O
+by,O
+denaturing,O
+gradient,O
+gel,O
+electrophoresis,O
+.,O
+ , 
+Mutations,O
+of,O
+the,O
+prion,B-Gene
+protein,I-Gene
+(,B-Gene
+PrP,I-Gene
+),I-Gene
+gene,O
+are,O
+present,O
+in,O
+patients,O
+with,O
+Gerstmann,O
+-,O
+Sträussler,O
+-,O
+Scheinker,O
+syndrome,O
+(,O
+GSS,O
+),O
+,,O
+familial,O
+Creutzfeldt,O
+-,O
+Jakob,O
+disease,O
+(,O
+CJD,O
+),O
+,,O
+and,O
+fatal,O
+familial,O
+insomnia,O
+(,O
+FFI,O
+),O
+.,O
+ , 
+We,O
+developed,O
+a,O
+denaturing,O
+gradient,O
+gel,O
+electrophoresis,O
+(,O
+DGGE,O
+),O
+strategy,O
+that,O
+readily,O
+identifies,O
+point,O
+mutations,O
+in,O
+the,O
+PrP,O
+coding,O
+sequence,O
+.,O
+ , 
+By,O
+comparison,O
+with,O
+appropriate,O
+controls,O
+,,O
+haplotypes,O
+often,O
+may,O
+be,O
+deduced,O
+.,O
+ , 
+This,O
+method,O
+permits,O
+samples,O
+from,O
+many,O
+patients,O
+with,O
+GSS,O
+,,O
+CJD,O
+,,O
+as,O
+well,O
+as,O
+patients,O
+with,O
+unusual,O
+degenerative,O
+neurologic,O
+disorders,O
+,,O
+to,O
+be,O
+screened,O
+rapidly,O
+,,O
+sensitively,O
+,,O
+and,O
+inexpensively,O
+for,O
+the,O
+presence,O
+of,O
+known,O
+and,O
+novel,O
+PrP,O
+mutations,O
+.,O
+ , 
+We,O
+illustrate,O
+the,O
+sensitivity,O
+of,O
+this,O
+approach,O
+by,O
+reporting,O
+2,O
+novel,O
+polymorphisms,O
+in,O
+the,O
+PrP,O
+coding,O
+sequence,O
+.,O
+ , 
+#14517964
+BUB1,B-Gene
+infrequently,O
+mutated,O
+in,O
+human,O
+breast,O
+carcinomas,O
+.,O
+ , 
+The,O
+BUB1,B-Gene
+gene,O
+is,O
+a,O
+key,O
+player,O
+in,O
+the,O
+mitotic,O
+spindle,O
+checkpoint,O
+machinery,O
+that,O
+monitors,O
+proper,O
+segregation,O
+of,O
+sister,O
+chromatides,O
+during,O
+mitosis,O
+.,O
+ , 
+It,O
+has,O
+been,O
+suggested,O
+that,O
+mutations,O
+in,O
+BUB1,B-Gene
+may,O
+disrupt,O
+the,O
+spindle,O
+checkpoint,O
+and,O
+thereby,O
+cause,O
+chromosomal,O
+instability,O
+,,O
+which,O
+is,O
+a,O
+hallmark,O
+of,O
+solid,O
+tumors,O
+including,O
+those,O
+from,O
+the,O
+breast,O
+.,O
+ , 
+From,O
+a,O
+series,O
+of,O
+breast,O
+carcinomas,O
+we,O
+selected,O
+20,O
+cases,O
+with,O
+genomic,O
+instability,O
+,,O
+as,O
+scored,O
+by,O
+Comparative,B-Gene
+Genome,I-Gene
+Hybridization,I-Gene
+(,B-Gene
+CGH,I-Gene
+),I-Gene
+,,O
+and,O
+without,O
+somatic,O
+TP53,B-Gene
+(,B-Gene
+p53,I-Gene
+),I-Gene
+mutations,O
+,,O
+and,O
+sequenced,O
+the,O
+entire,O
+coding,O
+region,O
+of,O
+the,O
+BUB1,B-Gene
+gene,O
+.,O
+ , 
+Two,O
+different,O
+constitutional,O
+sequence,O
+variants,O
+were,O
+found,O
+;,O
+a,O
+base,O
+substitution,O
+in,O
+exon,O
+5,O
+,,O
+c.481G,B-SNP
+>,I-SNP
+A,I-SNP
+(,O
+CAG,O
+>,O
+CAA,O
+,,O
+a,O
+synonymous,O
+change,O
+encoding,O
+Gln144,O
+),O
+in,O
+two,O
+samples,O
+,,O
+and,O
+a,O
+base,O
+substitution,O
+8,O
+bp,O
+upstream,O
+of,O
+exon,O
+10,O
+,,O
+c.1007,B-SNP
+-,I-SNP
+8T,I-SNP
+>,I-SNP
+C,I-SNP
+in,O
+two,O
+other,O
+samples,O
+.,O
+ , 
+No,O
+somatic,O
+mutations,O
+were,O
+detected,O
+.,O
+ , 
+These,O
+results,O
+indicate,O
+that,O
+genomic,O
+instability,O
+scored,O
+as,O
+copy,O
+number,O
+alterations,O
+by,O
+CGH,O
+in,O
+TP53,B-Gene
+wild,O
+type,O
+breast,O
+carcinomas,O
+is,O
+not,O
+caused,O
+by,O
+somatic,O
+mutations,O
+in,O
+the,O
+BUB1,B-Gene
+gene,O
+.,O
+ , 
+#18656178
+A,O
+comparative,O
+analysis,O
+of,O
+the,O
+genetic,O
+epidemiology,O
+of,O
+deafness,O
+in,O
+the,O
+United,O
+States,O
+in,O
+two,O
+sets,O
+of,O
+pedigrees,O
+collected,O
+more,O
+than,O
+a,O
+century,O
+apart,O
+.,O
+ , 
+In,O
+1898,O
+,,O
+E.A.,O
+Fay,O
+published,O
+an,O
+analysis,O
+of,O
+nearly,O
+5000,O
+marriages,O
+among,O
+deaf,O
+individuals,O
+in,O
+America,O
+collected,O
+during,O
+the,O
+19(th,O
+),O
+century,O
+.,O
+ , 
+Each,O
+pedigree,O
+included,O
+three,O
+-,O
+generation,O
+data,O
+on,O
+marriage,O
+partners,O
+that,O
+included,O
+at,O
+least,O
+one,O
+deaf,O
+proband,O
+,,O
+who,O
+were,O
+ascertained,O
+by,O
+complete,O
+selection,O
+.,O
+ , 
+We,O
+recently,O
+proposed,O
+that,O
+the,O
+intense,O
+phenotypic,O
+assortative,O
+mating,O
+among,O
+the,O
+deaf,O
+might,O
+have,O
+greatly,O
+accelerated,O
+the,O
+normally,O
+slow,O
+response,O
+to,O
+relaxed,O
+genetic,O
+selection,O
+against,O
+deafness,O
+that,O
+began,O
+in,O
+many,O
+Western,O
+countries,O
+with,O
+the,O
+introduction,O
+of,O
+sign,O
+language,O
+and,O
+the,O
+establishment,O
+of,O
+residential,O
+schools,O
+.,O
+ , 
+Simulation,O
+studies,O
+suggest,O
+that,O
+this,O
+mechanism,O
+might,O
+have,O
+doubled,O
+the,O
+frequency,O
+of,O
+the,O
+commonest,O
+forms,O
+of,O
+recessive,O
+deafness,O
+(,O
+DFNB1,O
+),O
+in,O
+this,O
+country,O
+during,O
+the,O
+past,O
+200,O
+years,O
+.,O
+ , 
+To,O
+test,O
+this,O
+prediction,O
+,,O
+we,O
+collected,O
+pedigree,O
+data,O
+on,O
+311,O
+contemporary,O
+marriages,O
+among,O
+deaf,O
+individuals,O
+that,O
+were,O
+comparable,O
+to,O
+those,O
+collected,O
+by,O
+Fay,O
+.,O
+ , 
+Segregation,O
+analysis,O
+of,O
+the,O
+resulting,O
+data,O
+revealed,O
+that,O
+the,O
+estimated,O
+proportion,O
+of,O
+noncomplementary,O
+matings,O
+that,O
+can,O
+produce,O
+only,O
+deaf,O
+children,O
+has,O
+increased,O
+by,O
+a,O
+factor,O
+of,O
+more,O
+than,O
+five,O
+in,O
+the,O
+past,O
+100,O
+years,O
+.,O
+ , 
+Additional,O
+analysis,O
+within,O
+our,O
+sample,O
+of,O
+contemporary,O
+pedigrees,O
+showed,O
+that,O
+there,O
+was,O
+a,O
+statistically,O
+significant,O
+linear,O
+increase,O
+in,O
+the,O
+prevalence,O
+of,O
+pathologic,O
+GJB2,B-Gene
+mutations,O
+when,O
+the,O
+data,O
+on,O
+441,O
+probands,O
+were,O
+partitioned,O
+into,O
+three,O
+20,O
+-,O
+year,O
+birth,O
+cohorts,O
+(,O
+1920,O
+through,O
+1980,O
+),O
+.,O
+ , 
+These,O
+data,O
+are,O
+consistent,O
+with,O
+the,O
+increase,O
+in,O
+the,O
+frequency,O
+of,O
+DFNB1,O
+predicted,O
+by,O
+our,O
+previous,O
+simulation,O
+studies,O
+and,O
+provide,O
+convincing,O
+evidence,O
+for,O
+the,O
+important,O
+influence,O
+that,O
+assortative,O
+mating,O
+can,O
+have,O
+on,O
+the,O
+frequency,O
+of,O
+common,O
+genes,O
+for,O
+deafness,O
+.,O
+ , 
+#18371931
+Loss,O
+of,O
+nephrocystin-3,B-Gene
+function,O
+can,O
+cause,O
+embryonic,O
+lethality,O
+,,O
+Meckel,O
+-,O
+Gruber,O
+-,O
+like,O
+syndrome,O
+,,O
+situs,O
+inversus,O
+,,O
+and,O
+renal,O
+-,O
+hepatic,O
+-,O
+pancreatic,O
+dysplasia,O
+.,O
+ , 
+Many,O
+genetic,O
+diseases,O
+have,O
+been,O
+linked,O
+to,O
+the,O
+dysfunction,O
+of,O
+primary,O
+cilia,O
+,,O
+which,O
+occur,O
+nearly,O
+ubiquitously,O
+in,O
+the,O
+body,O
+and,O
+act,O
+as,O
+solitary,O
+cellular,O
+mechanosensory,O
+organelles,O
+.,O
+ , 
+The,O
+list,O
+of,O
+clinical,O
+manifestations,O
+and,O
+affected,O
+tissues,O
+in,O
+cilia,O
+-,O
+related,O
+disorders,O
+(,O
+ciliopathies,O
+),O
+such,O
+as,O
+nephronophthisis,O
+is,O
+broad,O
+and,O
+has,O
+been,O
+attributed,O
+to,O
+the,O
+wide,O
+expression,O
+pattern,O
+of,O
+ciliary,O
+proteins,O
+.,O
+ , 
+However,O
+,,O
+little,O
+is,O
+known,O
+about,O
+the,O
+molecular,O
+mechanisms,O
+leading,O
+to,O
+this,O
+dramatic,O
+diversity,O
+of,O
+phenotypes,O
+.,O
+ , 
+We,O
+recently,O
+reported,O
+hypomorphic,O
+NPHP3,B-Gene
+mutations,O
+in,O
+children,O
+and,O
+young,O
+adults,O
+with,O
+isolated,O
+nephronophthisis,O
+and,O
+associated,O
+hepatic,O
+fibrosis,O
+or,O
+tapetoretinal,O
+degeneration,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+chose,O
+a,O
+combinatorial,O
+approach,O
+in,O
+mice,O
+and,O
+humans,O
+to,O
+define,O
+the,O
+phenotypic,O
+spectrum,O
+of,O
+NPHP3,B-Gene
+/,I-Gene
+Nphp3,I-Gene
+mutations,O
+and,O
+the,O
+role,O
+of,O
+the,O
+nephrocystin-3,B-Gene
+protein,O
+.,O
+ , 
+We,O
+demonstrate,O
+that,O
+the,O
+pcy,O
+mutation,O
+generates,O
+a,O
+hypomorphic,O
+Nphp3,B-Gene
+allele,O
+that,O
+is,O
+responsible,O
+for,O
+the,O
+cystic,O
+kidney,O
+disease,O
+phenotype,O
+,,O
+whereas,O
+complete,O
+loss,O
+of,O
+Nphp3,B-Gene
+function,O
+results,O
+in,O
+situs,O
+inversus,O
+,,O
+congenital,O
+heart,O
+defects,O
+,,O
+and,O
+embryonic,O
+lethality,O
+in,O
+mice,O
+.,O
+ , 
+In,O
+humans,O
+,,O
+we,O
+show,O
+that,O
+NPHP3,B-Gene
+mutations,O
+can,O
+cause,O
+a,O
+broad,O
+clinical,O
+spectrum,O
+of,O
+early,O
+embryonic,O
+patterning,O
+defects,O
+comprising,O
+situs,O
+inversus,O
+,,O
+polydactyly,O
+,,O
+central,O
+nervous,O
+system,O
+malformations,O
+,,O
+structural,O
+heart,O
+defects,O
+,,O
+preauricular,O
+fistulas,O
+,,O
+and,O
+a,O
+wide,O
+range,O
+of,O
+congenital,O
+anomalies,O
+of,O
+the,O
+kidney,O
+and,O
+urinary,O
+tract,O
+(,O
+CAKUT,O
+),O
+.,O
+ , 
+On,O
+the,O
+functional,O
+level,O
+,,O
+we,O
+show,O
+that,O
+nephrocystin-3,B-Gene
+directly,O
+interacts,O
+with,O
+inversin,O
+and,O
+can,O
+inhibit,O
+like,O
+inversin,O
+canonical,O
+Wnt,O
+signaling,O
+,,O
+whereas,O
+nephrocystin-3,B-Gene
+deficiency,O
+leads,O
+in,O
+Xenopus,O
+laevis,O
+to,O
+typical,O
+planar,O
+cell,O
+polarity,O
+defects,O
+,,O
+suggesting,O
+a,O
+role,O
+in,O
+the,O
+control,O
+of,O
+canonical,O
+and,O
+noncanonical,O
+(,O
+planar,O
+cell,O
+polarity,O
+),O
+ , 
+Wnt,O
+signaling,O
+.,O
+ , 
+#12970847
+Recent,O
+advances,O
+in,O
+human,O
+quantitative,O
+-,O
+trait,O
+-,O
+locus,O
+mapping,O
+:,O
+comparison,O
+of,O
+methods,O
+for,O
+selected,O
+sibling,O
+pairs,O
+.,O
+ , 
+During,O
+the,O
+past,O
+few,O
+years,O
+,,O
+there,O
+has,O
+been,O
+a,O
+great,O
+deal,O
+of,O
+new,O
+work,O
+on,O
+methods,O
+for,O
+mapping,O
+quantitative,O
+-,O
+trait,O
+loci,O
+by,O
+use,O
+of,O
+sibling,O
+pairs,O
+and,O
+sibships,O
+.,O
+ , 
+There,O
+are,O
+several,O
+new,O
+methods,O
+based,O
+on,O
+linear,O
+regression,O
+,,O
+as,O
+well,O
+as,O
+several,O
+more,O
+that,O
+are,O
+based,O
+on,O
+score,O
+statistics,O
+.,O
+ , 
+In,O
+theory,O
+,,O
+most,O
+of,O
+the,O
+new,O
+methods,O
+should,O
+be,O
+relatively,O
+robust,O
+to,O
+violations,O
+of,O
+distributional,O
+assumptions,O
+and,O
+to,O
+selected,O
+sampling,O
+,,O
+but,O
+,,O
+in,O
+practice,O
+,,O
+there,O
+has,O
+been,O
+little,O
+evaluation,O
+of,O
+how,O
+the,O
+methods,O
+perform,O
+on,O
+selected,O
+samples,O
+.,O
+ , 
+We,O
+survey,O
+most,O
+of,O
+the,O
+new,O
+regression,O
+-,O
+based,O
+statistics,O
+and,O
+score,O
+statistics,O
+and,O
+propose,O
+a,O
+few,O
+minor,O
+variations,O
+on,O
+the,O
+score,O
+statistics,O
+.,O
+ , 
+We,O
+use,O
+simulation,O
+to,O
+evaluate,O
+the,O
+type,O
+I,O
+error,O
+and,O
+the,O
+power,O
+of,O
+all,O
+of,O
+the,O
+statistics,O
+,,O
+considering,O
+(,O
+a,O
+),O
+population,O
+samples,O
+of,O
+sibling,O
+pairs,O
+and,O
+(,O
+b,O
+),O
+sibling,O
+pairs,O
+ascertained,O
+on,O
+the,O
+basis,O
+of,O
+at,O
+least,O
+one,O
+sibling,O
+with,O
+a,O
+trait,O
+value,O
+in,O
+the,O
+top,O
+10,O
+%,O
+of,O
+the,O
+distribution,O
+.,O
+ , 
+Most,O
+of,O
+the,O
+statistics,O
+have,O
+correct,O
+type,O
+I,O
+error,O
+for,O
+selected,O
+samples,O
+.,O
+ , 
+The,O
+statistics,O
+proposed,O
+by,O
+Xu,O
+et,O
+al,O
+.,O
+ , 
+and,O
+by,O
+Sham,O
+and,O
+Purcell,O
+are,O
+generally,O
+the,O
+most,O
+powerful,O
+,,O
+along,O
+with,O
+one,O
+of,O
+our,O
+score,O
+statistic,O
+variants,O
+.,O
+ , 
+Even,O
+among,O
+the,O
+methods,O
+that,O
+are,O
+most,O
+powerful,O
+for,O
+",O
+nice,O
+",O
+data,O
+,,O
+some,O
+are,O
+more,O
+robust,O
+than,O
+others,O
+to,O
+non,O
+-,O
+Gaussian,O
+trait,O
+models,O
+and/or,O
+misspecified,O
+trait,O
+parameters,O
+.,O
+ , 
+#11968091
+GJB2,B-Gene
+mutations,O
+in,O
+Iranians,O
+with,O
+autosomal,O
+recessive,O
+non,O
+-,O
+syndromic,O
+sensorineural,O
+hearing,O
+loss,O
+.,O
+ , 
+Hereditary,O
+hearing,O
+loss,O
+(,O
+HHL,O
+),O
+is,O
+an,O
+extremely,O
+common,O
+disorder,O
+.,O
+ , 
+About,O
+70,O
+%,O
+of,O
+HHL,O
+is,O
+non,O
+-,O
+syndromic,O
+,,O
+with,O
+autosomal,O
+recessive,O
+forms,O
+accounting,O
+for,O
+approximately,O
+85,O
+%,O
+of,O
+the,O
+genetic,O
+load,O
+.,O
+ , 
+Although,O
+very,O
+heterogeneous,O
+,,O
+the,O
+most,O
+common,O
+cause,O
+of,O
+HHL,O
+in,O
+many,O
+different,O
+world,O
+populations,O
+is,O
+mutations,O
+of,O
+GJB2,B-Gene
+,,I-Gene
+a,O
+gene,O
+that,O
+encodes,O
+the,O
+gap,O
+junction,O
+protein,O
+connexin,B-Gene
+26,I-Gene
+(,B-Gene
+Cx26,I-Gene
+),I-Gene
+.,O
+ , 
+This,O
+study,O
+investigates,O
+the,O
+contribution,O
+of,O
+GJB2,B-Gene
+to,O
+the,O
+autosomal,O
+recessive,O
+non,O
+-,O
+syndromic,O
+deafness,O
+(,O
+ARNSD,O
+),O
+load,O
+in,O
+the,O
+Iranian,O
+population,O
+.,O
+ , 
+One,O
+hundred,O
+sixty,O
+eight,O
+persons,O
+from,O
+83,O
+families,O
+were,O
+studied,O
+.,O
+ , 
+GJB2,B-Gene
+-,I-Gene
+related,O
+deafness,O
+was,O
+diagnosed,O
+in,O
+9,O
+families,O
+(,O
+4,O
+,,O
+35delG,B-SNP
+homozygotes,O
+;,O
+3,O
+,,O
+35delG,B-SNP
+compound,O
+heterozygotes,O
+;,O
+1,O
+,,O
+W24X,B-SNP
+homozygote,O
+;,O
+1,O
+,,O
+non-35delG,B-SNP
+compound,O
+heterozygote,O
+),O
+.,O
+ , 
+The,O
+carrier,O
+frequency,O
+of,O
+the,O
+35delG,B-SNP
+allele,O
+in,O
+this,O
+population,O
+was,O
+approximately,O
+1,O
+%,O
+(,O
+1/83,O
+),O
+.,O
+ , 
+Because,O
+the,O
+relative,O
+frequency,O
+of,O
+Cx26,B-Gene
+mutations,O
+is,O
+much,O
+less,O
+than,O
+in,O
+the,O
+other,O
+populations,O
+,,O
+it,O
+is,O
+possible,O
+that,O
+mutations,O
+in,O
+other,O
+genes,O
+play,O
+a,O
+major,O
+role,O
+in,O
+ARNSD,O
+in,O
+Iran,O
+.,O
+ , 
+#18452888
+Deleterious,O
+mutations,O
+in,O
+the,O
+Zinc,B-Gene
+-,I-Gene
+Finger,I-Gene
+469,I-Gene
+gene,O
+cause,O
+brittle,O
+cornea,O
+syndrome,O
+.,O
+ , 
+Brittle,O
+cornea,O
+syndrome,O
+(,O
+BCS,O
+),O
+is,O
+an,O
+autosomal,O
+-,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+a,O
+thin,O
+cornea,O
+that,O
+tends,O
+to,O
+perforate,O
+,,O
+causing,O
+progressive,O
+visual,O
+loss,O
+and,O
+blindness,O
+.,O
+ , 
+Additional,O
+systemic,O
+symptoms,O
+such,O
+as,O
+joint,O
+hypermotility,O
+,,O
+hyperlaxity,O
+of,O
+the,O
+skin,O
+,,O
+and,O
+kyphoscoliosis,O
+place,O
+BCS,O
+among,O
+the,O
+connective,O
+-,O
+tissue,O
+disorders,O
+.,O
+ , 
+Previously,O
+,,O
+we,O
+assigned,O
+the,O
+disease,O
+gene,O
+to,O
+a,O
+4.7,O
+Mb,O
+interval,O
+on,O
+chromosome,O
+16q24,O
+.,O
+ , 
+In,O
+order,O
+to,O
+clone,O
+the,O
+BCS,O
+gene,O
+,,O
+we,O
+first,O
+narrowed,O
+the,O
+disease,O
+locus,O
+to,O
+a,O
+2.8,O
+Mb,O
+interval,O
+and,O
+systematically,O
+sequenced,O
+genes,O
+expressed,O
+in,O
+connective,O
+tissue,O
+in,O
+this,O
+chromosomal,O
+segment,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+two,O
+frameshift,O
+mutations,O
+in,O
+the,O
+Zinc,B-Gene
+-,I-Gene
+Finger,I-Gene
+469,I-Gene
+gene,O
+(,B-Gene
+ZNF469,I-Gene
+),I-Gene
+.,O
+ , 
+In,O
+five,O
+unrelated,O
+patients,O
+of,O
+Tunisian,O
+Jewish,O
+ancestry,O
+,,O
+we,O
+found,O
+a,O
+1,O
+bp,O
+deletion,O
+at,O
+position,O
+5943,O
+(,B-SNP
+5943,I-SNP
+delA,I-SNP
+),I-SNP
+,,O
+and,O
+in,O
+an,O
+inbred,O
+Palestinian,O
+family,O
+we,O
+detected,O
+a,O
+single,O
+-,O
+nucleotide,O
+deletion,O
+at,O
+position,O
+9527,O
+(,B-SNP
+9527,I-SNP
+delG,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+function,O
+of,O
+ZNF469,B-Gene
+is,O
+unknown,O
+.,O
+ , 
+However,O
+,,O
+a,O
+30,O
+%,O
+homology,O
+to,O
+a,O
+number,O
+of,O
+collagens,O
+suggests,O
+that,O
+it,O
+could,O
+act,O
+as,O
+a,O
+transcription,O
+factor,O
+involved,O
+in,O
+the,O
+synthesis,O
+and/or,O
+organization,O
+of,O
+collagen,O
+fibers,O
+.,O
+ , 
+#8535441
+Comparison,O
+between,O
+medium,O
+-,O
+chain,O
+acyl,B-Gene
+-,I-Gene
+CoA,I-Gene
+dehydrogenase,I-Gene
+mutant,O
+proteins,O
+overexpressed,O
+in,O
+bacterial,O
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+cells,O
+.,O
+ , 
+Medium,B-Gene
+-,I-Gene
+chain,I-Gene
+acyl,I-Gene
+-,I-Gene
+CoA,I-Gene
+dehydrogenase,I-Gene
+(,B-Gene
+MCAD,I-Gene
+),I-Gene
+deficiency,O
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+a,O
+potentially,O
+lethal,O
+inherited,O
+defect,O
+in,O
+the,O
+beta,O
+-,O
+oxidation,O
+of,O
+fatty,O
+acids,O
+.,O
+ , 
+By,O
+comparing,O
+the,O
+behaviour,O
+of,O
+five,O
+missense,O
+MCAD,B-Gene
+mutant,O
+proteins,O
+expressed,O
+in,O
+COS,O
+cells,O
+and,O
+in,O
+Escherichia,O
+coli,O
+,,O
+we,O
+can,O
+define,O
+some,O
+of,O
+these,O
+as,O
+",O
+pure,O
+folding,O
+mutants,O
+.,O
+",O
+ , 
+Upon,O
+expression,O
+in,O
+E.,O
+coli,O
+,,O
+these,O
+mutant,O
+proteins,O
+produce,O
+activity,O
+levels,O
+in,O
+the,O
+range,O
+of,O
+the,O
+wild,O
+-,O
+type,O
+enzyme,O
+only,O
+if,O
+the,O
+chaperonins,O
+GroESL,O
+are,O
+co,O
+-,O
+overproduced,O
+.,O
+ , 
+When,O
+overexpressed,O
+in,O
+COS,O
+cells,O
+,,O
+the,O
+pure,O
+folding,O
+mutants,O
+display,O
+enzyme,O
+activities,O
+comparable,O
+to,O
+the,O
+wild,O
+-,O
+type,O
+enzyme,O
+.,O
+ , 
+The,O
+results,O
+suggest,O
+that,O
+the,O
+MCAD,B-Gene
+mutations,O
+can,O
+be,O
+modulated,O
+by,O
+chaperones,O
+,,O
+a,O
+phenomenon,O
+that,O
+may,O
+influence,O
+the,O
+manifestation,O
+of,O
+the,O
+MCAD,O
+disease,O
+.,O
+ , 
+#8535449
+A,O
+48,O
+-,O
+bp,O
+insertion,O
+between,O
+exon,O
+13,O
+and,O
+14,O
+of,O
+the,O
+HEXB,B-Gene
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+infantile,O
+-,O
+onset,O
+Sandhoff,O
+disease,O
+.,O
+ , 
+#12958705
+Genomewide,O
+linkage,O
+and,O
+linkage,O
+disequilibrium,O
+analyses,O
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+COL6A1,B-Gene
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+chromosome,O
+21,O
+,,O
+as,O
+the,O
+locus,O
+for,O
+ossification,O
+of,O
+the,O
+posterior,O
+longitudinal,O
+ligament,O
+of,O
+the,O
+spine,O
+.,O
+ , 
+Ossification,O
+of,O
+the,O
+posterior,O
+longitudinal,O
+ligament,O
+(,O
+OPLL,O
+),O
+of,O
+the,O
+spine,O
+is,O
+a,O
+subset,O
+of,O
+",O
+bone,O
+-,O
+forming,O
+",O
+diseases,O
+,,O
+characterized,O
+by,O
+ectopic,O
+ossification,O
+in,O
+the,O
+spinal,O
+ligaments,O
+.,O
+ , 
+OPLL,O
+is,O
+a,O
+common,O
+disorder,O
+among,O
+elderly,O
+populations,O
+in,O
+eastern,O
+Asia,O
+and,O
+is,O
+the,O
+leading,O
+cause,O
+of,O
+spinal,O
+myelopathy,O
+in,O
+Japan,O
+.,O
+ , 
+We,O
+performed,O
+a,O
+genomewide,O
+linkage,O
+study,O
+with,O
+142,O
+affected,O
+sib,O
+pairs,O
+,,O
+to,O
+identify,O
+genetic,O
+loci,O
+related,O
+to,O
+OPLL,O
+.,O
+ , 
+In,O
+multipoint,O
+linkage,O
+analysis,O
+using,O
+GENEHUNTER,O
+-,O
+PLUS,O
+,,O
+evidence,O
+of,O
+linkage,O
+to,O
+OPLL,O
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+detected,O
+on,O
+chromosomes,O
+1p,O
+,,O
+6p,O
+,,O
+11q,O
+,,O
+14q,O
+,,O
+16q,O
+,,O
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+21q,O
+.,O
+ , 
+The,O
+best,O
+evidence,O
+of,O
+linkage,O
+was,O
+detected,O
+near,O
+D21S1903,O
+on,O
+chromosome,O
+21q22.3,O
+(,O
+maximum,O
+Zlr=3.97,O
+),O
+;,O
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+,,O
+the,O
+linkage,O
+region,O
+was,O
+extensively,O
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+for,O
+linkage,O
+disequilibrium,O
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+single,O
+-,O
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+(,O
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+),O
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+20,O
+Mb,O
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+One,O
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+genes,O
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+region,O
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+600,O
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+There,O
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+seven,O
+genes,O
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+280,O
+patients,O
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+210,O
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+,,O
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+seven,O
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+within,O
+a,O
+region,O
+of,O
+750,O
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+.,O
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+Extensive,O
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+of,O
+the,O
+four,O
+genes,O
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+that,O
+SNPs,O
+in,O
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+collagen,B-Gene
+6A1,I-Gene
+gene,O
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+COL6A1,I-Gene
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+OPLL,O
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+SNP,O
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+32,O
+ , 
+[,O
+-29,O
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+),O
+.,O
+ , 
+Haplotype,O
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+three,O
+SNPs,O
+in,O
+COL6A1,B-Gene
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+-,O
+point,O
+P,O
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+Identification,O
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+locus,O
+of,O
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+to,O
+OPLL,O
+by,O
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+linkage,O
+and,O
+linkage,O
+disequilibrium,O
+studies,O
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+us,O
+to,O
+investigate,O
+the,O
+pathogenesis,O
+of,O
+the,O
+disease,O
+,,O
+which,O
+may,O
+lead,O
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+the,O
+development,O
+of,O
+novel,O
+therapeutic,O
+tools,O
+.,O
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+#14658095
+Linkage,O
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+(,O
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+a,O
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+.,O
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+Clinical,O
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+reinforced,O
+by,O
+epidemiology,O
+and,O
+genetics,O
+,,O
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+impressive,O
+variation,O
+in,O
+disease,O
+severity,O
+,,O
+expression,O
+,,O
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+,,O
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+incidence,O
+by,O
+ethnicity,O
+and,O
+sex,O
+.,O
+ , 
+To,O
+identify,O
+the,O
+novel,O
+SLE,O
+susceptibility,O
+loci,O
+,,O
+we,O
+performed,O
+a,O
+genomewide,O
+scan,O
+with,O
+318,O
+markers,O
+on,O
+37,O
+multiplex,O
+Hispanic,O
+families,O
+,,O
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+a,O
+nonparametric,O
+penetrance,O
+-,O
+independent,O
+affected,O
+-,O
+only,O
+allele,O
+-,O
+sharing,O
+method,O
+.,O
+ , 
+Three,O
+chromosomal,O
+regions,O
+(,O
+12q24,O
+,,O
+16p13,O
+,,O
+and,O
+16q12,O
+-,O
+21,O
+),O
+exceeded,O
+our,O
+predetermined,O
+threshold,O
+(,O
+Zlr>2.32,O
+;,O
+nominal,O
+P<.01,O
+),O
+for,O
+further,O
+evaluation,O
+.,O
+ , 
+Suspected,O
+linkages,O
+at,O
+12q24,O
+,,O
+16p13,O
+,,O
+and,O
+16q12,O
+-,O
+21,O
+were,O
+tested,O
+in,O
+an,O
+independent,O
+data,O
+set,O
+consisting,O
+of,O
+92,O
+European,O
+American,O
+(,O
+EA-1,O
+),O
+and,O
+55,O
+African,O
+American,O
+(,O
+AA,O
+),O
+families,O
+.,O
+ , 
+The,O
+linkage,O
+at,O
+12q24,O
+was,O
+replicated,O
+in,O
+EA-1,O
+(,O
+Zlr=3.06,O
+;,O
+P=.001,O
+),O
+but,O
+not,O
+in,O
+AA,O
+(,O
+Zlr=0.37,O
+;,O
+P=.35,O
+),O
+.,O
+ , 
+Although,O
+neither,O
+the,O
+16p13,O
+nor,O
+the,O
+16q12,O
+-,O
+21,O
+was,O
+confirmed,O
+in,O
+EA-1,O
+or,O
+AA,O
+,,O
+the,O
+suggestive,O
+linkage,O
+(,O
+Zlr=3.06,O
+;,O
+P=.001,O
+),O
+at,O
+16q12,O
+-,O
+21,O
+is,O
+sufficient,O
+to,O
+confirm,O
+the,O
+significant,O
+linkage,O
+,,O
+reported,O
+elsewhere,O
+,,O
+at,O
+this,O
+location,O
+.,O
+ , 
+The,O
+evidence,O
+for,O
+linkage,O
+at,O
+12q24,O
+in,O
+the,O
+129,O
+combined,O
+(,O
+Hispanic,O
+and,O
+EA-1,O
+),O
+families,O
+exceeded,O
+the,O
+threshold,O
+for,O
+genomewide,O
+significance,O
+(,O
+Zlr=4.39,O
+;,O
+P=5.7x10,O
+-,O
+6,O
+;,O
+nonparametric,O
+LOD=4.19,O
+),O
+.,O
+ , 
+Parametric,O
+linkage,O
+analyses,O
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+a,O
+low,O
+-,O
+penetrance,O
+,,O
+dominant,O
+model,O
+(,O
+LOD=3.72,O
+),O
+.,O
+ , 
+To,O
+confirm,O
+the,O
+linkage,O
+effect,O
+at,O
+12q24,O
+,,O
+we,O
+performed,O
+linkage,O
+analysis,O
+in,O
+another,O
+set,O
+of,O
+82,O
+independent,O
+European,O
+American,O
+families,O
+(,O
+EA-2,O
+),O
+.,O
+ , 
+The,O
+evidence,O
+for,O
+linkage,O
+was,O
+confirmed,O
+(,O
+Zlr=2.11,O
+;,O
+P=.017,O
+),O
+.,O
+ , 
+Therefore,O
+,,O
+our,O
+results,O
+have,O
+detected,O
+,,O
+established,O
+,,O
+and,O
+confirmed,O
+the,O
+existence,O
+of,O
+a,O
+novel,O
+SLE,O
+susceptibility,O
+locus,O
+at,O
+12q24,O
+(,O
+designated,O
+",O
+SLEB4,O
+",O
+),O
+that,O
+may,O
+cause,O
+lupus,O
+,,O
+especially,O
+in,O
+Hispanic,O
+and,O
+European,O
+American,O
+families,O
+.,O
+ , 
+#8940267
+Spectrum,O
+of,O
+mutations,O
+in,O
+the,O
+COL4A5,B-Gene
+collagen,O
+gene,O
+in,O
+X,O
+-,O
+linked,O
+Alport,O
+syndrome,O
+.,O
+ , 
+Alport,O
+syndrome,O
+is,O
+a,O
+mainly,O
+X,O
+-,O
+linked,O
+hereditary,O
+disease,O
+of,O
+basement,O
+membranes,O
+that,O
+is,O
+characterized,O
+by,O
+progressive,O
+renal,O
+failure,O
+,,O
+deafness,O
+,,O
+and,O
+ocular,O
+lesions,O
+.,O
+ , 
+It,O
+is,O
+associated,O
+with,O
+mutations,O
+of,O
+the,O
+COL4A5,B-Gene
+gene,O
+located,O
+at,O
+Xq22,O
+and,O
+encoding,O
+the,O
+alpha5,O
+chain,O
+of,O
+type,O
+IV,O
+collagen,O
+.,O
+ , 
+We,O
+have,O
+screened,O
+48,O
+of,O
+the,O
+51,O
+exons,O
+of,O
+the,O
+COL4A5,B-Gene
+gene,O
+by,O
+SSCP,O
+analysis,O
+and,O
+have,O
+identified,O
+64,O
+mutations,O
+and,O
+10,O
+sequence,O
+variants,O
+among,O
+131,O
+unrelated,O
+Alport,O
+syndrome,O
+patients,O
+.,O
+ , 
+This,O
+represents,O
+a,O
+mutation,O
+-,O
+detection,O
+rate,O
+of,O
+50,O
+%,O
+.,O
+ , 
+There,O
+were,O
+no,O
+hot,O
+-,O
+spot,O
+mutations,O
+and,O
+no,O
+recurrent,O
+mutations,O
+in,O
+our,O
+population,O
+.,O
+ , 
+The,O
+identified,O
+mutations,O
+were,O
+6,O
+nonsense,O
+mutations,O
+,,O
+12,O
+frameshift,O
+mutations,O
+,,O
+17,O
+splice,O
+-,O
+site,O
+mutations,O
+,,O
+and,O
+29,O
+missense,O
+mutations,O
+,,O
+27,O
+of,O
+the,O
+latter,O
+being,O
+glycine,O
+substitutions,O
+in,O
+the,O
+collagenous,O
+domain,O
+.,O
+ , 
+Two,O
+of,O
+these,O
+occurred,O
+on,O
+the,O
+same,O
+allele,O
+in,O
+one,O
+patient,O
+and,O
+segregated,O
+with,O
+the,O
+disease,O
+in,O
+the,O
+family,O
+.,O
+ , 
+We,O
+showed,O
+that,O
+some,O
+of,O
+the,O
+glycine,O
+substitutions,O
+could,O
+be,O
+associated,O
+with,O
+the,O
+lack,O
+of,O
+immunological,O
+expression,O
+of,O
+the,O
+alpha3(IV)-alpha5(IV,O
+),O
+collagen,O
+chains,O
+in,O
+the,O
+glomerular,O
+basement,O
+membrane,O
+.,O
+ , 
+#20920665
+Identification,O
+of,O
+copy,O
+number,O
+variation,O
+hotspots,O
+in,O
+human,O
+populations,O
+.,O
+ , 
+Copy,O
+number,O
+variants,O
+(,O
+CNVs,O
+),O
+in,O
+the,O
+human,O
+genome,O
+contribute,O
+to,O
+both,O
+Mendelian,O
+and,O
+complex,O
+traits,O
+as,O
+well,O
+as,O
+to,O
+genomic,O
+plasticity,O
+in,O
+evolution,O
+.,O
+ , 
+The,O
+investigation,O
+of,O
+mutational,O
+rates,O
+of,O
+CNVs,O
+is,O
+critical,O
+to,O
+understanding,O
+genomic,O
+instability,O
+and,O
+the,O
+etiology,O
+of,O
+the,O
+copy,O
+number,O
+variation,O
+(,O
+CNV)-related,O
+traits,O
+.,O
+ , 
+However,O
+,,O
+the,O
+evaluation,O
+of,O
+the,O
+CNV,O
+mutation,O
+rate,O
+at,O
+the,O
+genome,O
+level,O
+poses,O
+an,O
+insurmountable,O
+practical,O
+challenge,O
+that,O
+requires,O
+large,O
+samples,O
+and,O
+accurate,O
+typing,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+show,O
+that,O
+an,O
+approximate,O
+estimation,O
+of,O
+the,O
+CNV,O
+mutation,O
+rate,O
+could,O
+be,O
+achieved,O
+by,O
+using,O
+the,O
+phylogeny,O
+information,O
+of,O
+flanking,O
+SNPs,O
+.,O
+ , 
+This,O
+allows,O
+a,O
+genome,O
+-,O
+wide,O
+comparison,O
+of,O
+mutation,O
+rates,O
+between,O
+CNVs,O
+with,O
+the,O
+use,O
+of,O
+vast,O
+,,O
+readily,O
+available,O
+data,O
+of,O
+SNP,O
+genotyping,O
+.,O
+ , 
+A,O
+total,O
+of,O
+4187,O
+CNV,O
+regions,O
+(,O
+CNVRs,O
+),O
+previously,O
+identified,O
+in,O
+HapMap,O
+populations,O
+were,O
+investigated,O
+in,O
+this,O
+study,O
+.,O
+ , 
+We,O
+showed,O
+that,O
+the,O
+mutation,O
+rates,O
+for,O
+the,O
+majority,O
+of,O
+these,O
+CNVRs,O
+are,O
+at,O
+the,O
+order,O
+of,O
+10⁻⁵,O
+per,O
+generation,O
+,,O
+consistent,O
+with,O
+experimental,O
+observations,O
+at,O
+individual,O
+loci,O
+.,O
+ , 
+Notably,O
+,,O
+the,O
+mutation,O
+rates,O
+of,O
+104,O
+(,O
+2.5,O
+%,O
+),O
+CNVRs,O
+were,O
+estimated,O
+at,O
+the,O
+order,O
+of,O
+10⁻³,O
+per,O
+generation,O
+;,O
+therefore,O
+,,O
+they,O
+were,O
+identified,O
+as,O
+potential,O
+hotspots,O
+.,O
+ , 
+Additional,O
+analyses,O
+revealed,O
+that,O
+genome,O
+architecture,O
+at,O
+CNV,O
+loci,O
+has,O
+a,O
+potential,O
+role,O
+in,O
+inciting,O
+mutational,O
+hotspots,O
+in,O
+the,O
+human,O
+genome,O
+.,O
+ , 
+Interestingly,O
+,,O
+49,O
+(,O
+47,O
+%,O
+),O
+CNV,O
+hotspots,O
+include,O
+human,O
+genes,O
+,,O
+some,O
+of,O
+which,O
+are,O
+known,O
+to,O
+be,O
+functional,O
+CNV,O
+loci,O
+(,O
+e.g.,O
+,,O
+CNVs,O
+of,O
+C4,O
+and,O
+β,O
+-,O
+defensin,O
+causing,O
+autoimmune,O
+diseases,O
+and,O
+CNVs,O
+of,O
+HYDIN,B-Gene
+with,O
+implication,O
+in,O
+control,O
+of,O
+cerebral,O
+cortex,O
+size,O
+),O
+,,O
+implicating,O
+the,O
+important,O
+role,O
+of,O
+CNV,O
+in,O
+human,O
+health,O
+and,O
+evolution,O
+,,O
+especially,O
+in,O
+common,O
+and,O
+complex,O
+diseases,O
+.,O
+ , 
+#10631132
+Elevated,O
+levels,O
+of,O
+FMR1,B-Gene
+mRNA,O
+in,O
+carrier,O
+males,O
+:,O
+a,O
+new,O
+mechanism,O
+of,O
+involvement,O
+in,O
+the,O
+fragile,O
+-,O
+X,O
+syndrome,O
+.,O
+ , 
+Fragile,O
+-,O
+X,O
+syndrome,O
+is,O
+a,O
+trinucleotide,O
+-,O
+repeat,O
+-,O
+expansion,O
+disorder,O
+in,O
+which,O
+the,O
+clinical,O
+phenotype,O
+is,O
+believed,O
+to,O
+result,O
+from,O
+transcriptional,O
+silencing,O
+of,O
+the,O
+fragile,B-Gene
+-,I-Gene
+X,I-Gene
+mental,I-Gene
+retardation,I-Gene
+1,I-Gene
+(,B-Gene
+FMR1,I-Gene
+),I-Gene
+gene,O
+as,O
+the,O
+number,O
+of,O
+CGG,O
+repeats,O
+exceeds,O
+approximately,O
+200,O
+.,O
+ , 
+For,O
+premutation,O
+alleles,O
+(,O
+approximately,O
+55,O
+-,O
+200,O
+repeats,O
+),O
+,,O
+no,O
+abnormalities,O
+in,O
+FMR1,B-Gene
+-,I-Gene
+gene,O
+expression,O
+have,O
+been,O
+described,O
+,,O
+despite,O
+growing,O
+evidence,O
+of,O
+clinical,O
+involvement,O
+in,O
+premutation,O
+carriers,O
+.,O
+ , 
+To,O
+address,O
+this,O
+(,O
+apparent,O
+),O
+paradox,O
+,,O
+we,O
+have,O
+determined,O
+,,O
+for,O
+16,O
+carrier,O
+males,O
+(,O
+55,O
+-,O
+192,O
+repeats,O
+),O
+,,O
+the,O
+relative,O
+levels,O
+of,O
+leukocyte,O
+FMR1,O
+mRNA,O
+,,O
+by,O
+use,O
+of,O
+automated,O
+fluorescence,O
+-,O
+detection,O
+reverse,O
+transcriptase,O
+-,O
+PCR,O
+,,O
+and,O
+the,O
+percent,O
+of,O
+lymphocytes,O
+that,O
+are,O
+immunoreactive,O
+for,O
+FMR1,B-Gene
+protein,O
+(,B-Gene
+FMRP,I-Gene
+),I-Gene
+.,O
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+For,O
+some,O
+alleles,O
+with>100,O
+repeats,O
+,,O
+there,O
+was,O
+a,O
+reduction,O
+in,O
+the,O
+number,O
+of,O
+FMRP,O
+-,O
+positive,O
+cells,O
+.,O
+ , 
+Unexpectedly,O
+,,O
+FMR1,B-Gene
+mRNA,O
+levels,O
+were,O
+elevated,O
+at,O
+least,O
+fivefold,O
+within,O
+this,O
+same,O
+range,O
+.,O
+ , 
+No,O
+significant,O
+increase,O
+in,O
+FMR1,B-Gene
+mRNA,O
+stability,O
+was,O
+observed,O
+in,O
+a,O
+lymphoblastoid,O
+cell,O
+line,O
+(,O
+160,O
+repeats,O
+),O
+derived,O
+from,O
+one,O
+of,O
+the,O
+carrier,O
+males,O
+,,O
+suggesting,O
+that,O
+the,O
+increased,O
+message,O
+levels,O
+are,O
+due,O
+to,O
+an,O
+increased,O
+rate,O
+of,O
+transcription,O
+.,O
+ , 
+Current,O
+results,O
+support,O
+a,O
+mechanism,O
+of,O
+involvement,O
+in,O
+premutation,O
+carriers,O
+,,O
+in,O
+which,O
+reduced,O
+translational,O
+efficiency,O
+is,O
+at,O
+least,O
+partially,O
+compensated,O
+through,O
+increased,O
+transcriptional,O
+activity,O
+.,O
+ , 
+Thus,O
+,,O
+diminished,O
+translational,O
+efficiency,O
+may,O
+be,O
+important,O
+throughout,O
+much,O
+of,O
+the,O
+premutation,O
+range,O
+,,O
+with,O
+a,O
+mechanistic,O
+switch,O
+occurring,O
+in,O
+the,O
+full,O
+-,O
+mutation,O
+range,O
+as,O
+the,O
+FMR1,B-Gene
+gene,O
+is,O
+silenced,O
+.,O
+ , 
+#22387015
+Bent,O
+bone,O
+dysplasia,O
+-,O
+FGFR2,O
+type,O
+,,O
+a,O
+distinct,O
+skeletal,O
+disorder,O
+,,O
+has,O
+deficient,O
+canonical,O
+FGF,O
+signaling,O
+.,O
+ , 
+Fibroblast,B-Gene
+growth,I-Gene
+factor,I-Gene
+receptor,I-Gene
+2,I-Gene
+(,B-Gene
+FGFR2,I-Gene
+),I-Gene
+is,O
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+crucial,O
+regulator,O
+of,O
+bone,O
+formation,O
+during,O
+embryonic,O
+development,O
+.,O
+ , 
+Both,O
+gain,O
+and,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+studies,O
+in,O
+mice,O
+have,O
+shown,O
+that,O
+FGFR2,B-Gene
+maintains,O
+a,O
+critical,O
+balance,O
+between,O
+the,O
+proliferation,O
+and,O
+differentiation,O
+of,O
+osteoprogenitor,O
+cells,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+de,O
+novo,O
+FGFR2,B-Gene
+mutations,O
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+a,O
+sporadically,O
+occurring,O
+perinatal,O
+lethal,O
+skeletal,O
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+characterized,O
+by,O
+poor,O
+mineralization,O
+of,O
+the,O
+calvarium,O
+,,O
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+,,O
+dysmorphic,O
+facial,O
+features,O
+,,O
+prenatal,O
+teeth,O
+,,O
+hypoplastic,O
+pubis,O
+and,O
+clavicles,O
+,,O
+osteopenia,O
+,,O
+and,O
+bent,O
+long,O
+bones,O
+.,O
+ , 
+Histological,O
+analysis,O
+of,O
+the,O
+long,O
+bones,O
+revealed,O
+that,O
+the,O
+growth,O
+plate,O
+contained,O
+smaller,O
+hypertrophic,O
+chondrocytes,O
+and,O
+a,O
+thickened,O
+hypercellular,O
+periosteum,O
+.,O
+ , 
+Four,O
+unrelated,O
+affected,O
+individuals,O
+were,O
+found,O
+to,O
+be,O
+heterozygous,O
+for,O
+missense,O
+mutations,O
+that,O
+introduce,O
+a,O
+polar,O
+amino,O
+acid,O
+into,O
+the,O
+hydrophobic,O
+transmembrane,O
+domain,O
+of,O
+FGFR2,B-Gene
+.,I-Gene
+ , 
+Using,O
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+a,O
+cell,O
+-,O
+based,O
+assay,O
+,,O
+we,O
+determined,O
+that,O
+these,O
+mutations,O
+selectively,O
+reduced,O
+plasma,O
+-,O
+membrane,O
+levels,O
+of,O
+FGFR2,B-Gene
+and,O
+markedly,O
+diminished,O
+the,O
+receptor,O
+'s,O
+responsiveness,O
+to,O
+extracellular,O
+FGF,O
+.,O
+ , 
+All,O
+together,O
+,,O
+these,O
+clinical,O
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+molecular,O
+findings,O
+are,O
+separate,O
+from,O
+previously,O
+characterized,O
+FGFR2,B-Gene
+disorders,O
+and,O
+represent,O
+a,O
+distinct,O
+skeletal,O
+dysplasia,O
+.,O
+ , 
+#16211558
+Novel,O
+mutations,O
+of,O
+the,O
+PCSK9,B-Gene
+gene,O
+cause,O
+variable,O
+phenotype,O
+of,O
+autosomal,O
+dominant,O
+hypercholesterolemia,O
+.,O
+ , 
+Autosomal,O
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+hypercholesterolemia,O
+(,O
+ADH,O
+),O
+is,O
+a,O
+frequent,O
+(,O
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+),O
+monogenic,O
+inherited,O
+disorder,O
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+by,O
+isolated,O
+elevation,O
+of,O
+LDL,O
+leading,O
+to,O
+premature,O
+cardiovascular,O
+disease,O
+.,O
+ , 
+ADH,O
+is,O
+known,O
+to,O
+result,O
+from,O
+mutations,O
+at,O
+two,O
+main,O
+loci,O
+:,O
+LDLR,O
+(,O
+encoding,O
+the,O
+low,O
+density,O
+lipoprotein,O
+receptor,O
+),O
+,,O
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+APOB,O
+(,O
+encoding,O
+apolipoprotein,O
+B100,O
+),O
+,,O
+its,O
+natural,O
+ligand,O
+.,O
+ , 
+We,O
+previously,O
+demonstrated,O
+that,O
+ADH,O
+is,O
+also,O
+caused,O
+by,O
+mutations,O
+of,O
+the,O
+PCSK9,B-Gene
+(,B-Gene
+proprotein,I-Gene
+convertase,I-Gene
+subtilisin,I-Gene
+/,I-Gene
+kexin,I-Gene
+type,I-Gene
+9,I-Gene
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+gene,O
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+Narc-1,B-Gene
+(,B-Gene
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+regulated,I-Gene
+convertase,I-Gene
+1,I-Gene
+),I-Gene
+.,O
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+However,O
+,,O
+the,O
+role,O
+of,O
+this,O
+novel,O
+disease,O
+locus,O
+as,O
+a,O
+cause,O
+of,O
+hypercholesterolemia,O
+remains,O
+unclear,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+we,O
+analysed,O
+the,O
+PCSK9,B-Gene
+coding,O
+region,O
+and,O
+intronic,O
+junctions,O
+in,O
+130,O
+adult,O
+or,O
+pediatric,O
+patients,O
+with,O
+ADH,O
+,,O
+previously,O
+found,O
+as,O
+being,O
+non,O
+LDLR,O
+/,O
+non,O
+APOB,O
+mutation,O
+carriers,O
+.,O
+ , 
+Four,O
+novel,O
+heterozygous,O
+missense,O
+variations,O
+were,O
+found,O
+:,O
+c.654A,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+R218S,I-SNP
+),I-SNP
+,,O
+c.1070G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+R357H,I-SNP
+),I-SNP
+,,O
+c.1405C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+R469W,I-SNP
+),I-SNP
+,,O
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+c.1327G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+A443,I-SNP
+T,I-SNP
+),I-SNP
+.,O
+ , 
+All,O
+mutations,O
+were,O
+absent,O
+in,O
+340,O
+normolipidemic,O
+controls,O
+.,O
+ , 
+Except,O
+for,O
+the,O
+A443,B-SNP
+T,I-SNP
+,,I-SNP
+all,O
+mutations,O
+are,O
+nonconservative,O
+and,O
+modify,O
+a,O
+highly,O
+conserved,O
+residue,O
+.,O
+ , 
+Segregation,O
+with,O
+hypercholesterolemia,O
+is,O
+incomplete,O
+in,O
+one,O
+pedigree,O
+.,O
+ , 
+Type,O
+and,O
+severity,O
+of,O
+hyperlipidemia,O
+and,O
+of,O
+cardiovascular,O
+disease,O
+could,O
+vary,O
+among,O
+subjects,O
+from,O
+the,O
+same,O
+family,O
+.,O
+ , 
+Finally,O
+,,O
+the,O
+proband,O
+carrying,O
+the,O
+R357H,B-SNP
+mutation,O
+exhibited,O
+very,O
+high,O
+plasma,O
+cholesterol,O
+during,O
+pregnancy,O
+,,O
+whereas,O
+the,O
+proband,O
+carrying,O
+the,O
+p.,B-SNP
+R469W,I-SNP
+mutation,O
+exhibited,O
+a,O
+severe,O
+phenotype,O
+of,O
+hypercholesterolemia,O
+in,O
+combination,O
+with,O
+a,O
+LDLR,O
+mutation,O
+resulting,O
+from,O
+a,O
+frameshift,B-SNP
+at,I-SNP
+residue,I-SNP
+F382,I-SNP
+(,B-SNP
+1209delC,I-SNP
+),I-SNP
+.,O
+ , 
+These,O
+observations,O
+suggest,O
+that,O
+variations,O
+in,O
+PCSK9,B-Gene
+are,O
+a,O
+rare,O
+cause,O
+of,O
+non,O
+LDLR,O
+/,O
+non,O
+APOB,O
+ADH,O
+(,O
+approximately,O
+2.3,O
+%,O
+),O
+and,O
+that,O
+additional,O
+environmental,O
+or,O
+genetic,O
+factors,O
+may,O
+contribute,O
+to,O
+the,O
+phenotype,O
+caused,O
+by,O
+PCSK9,B-Gene
+missense,O
+mutations,O
+in,O
+humans,O
+.,O
+ , 
+#16080112
+Differential,O
+X,O
+reactivation,O
+in,O
+human,O
+placental,O
+cells,O
+:,O
+implications,O
+for,O
+reversal,O
+of,O
+X,O
+inactivation,O
+.,O
+ , 
+X,O
+inactivation,O
+--,O
+the,O
+mammalian,O
+method,O
+of,O
+X,O
+chromosome,O
+dosage,O
+compensation,O
+--,O
+is,O
+extremely,O
+stable,O
+in,O
+human,O
+somatic,O
+cells,O
+;,O
+only,O
+fetal,O
+germ,O
+cells,O
+have,O
+a,O
+developmental,O
+program,O
+to,O
+reverse,O
+the,O
+process,O
+.,O
+ , 
+The,O
+human,O
+placenta,O
+,,O
+at,O
+term,O
+,,O
+differs,O
+from,O
+other,O
+somatic,O
+tissues,O
+,,O
+since,O
+it,O
+has,O
+the,O
+ability,O
+to,O
+reverse,O
+the,O
+X,O
+-,O
+inactivation,O
+program,O
+.,O
+ , 
+To,O
+determine,O
+whether,O
+reversal,O
+can,O
+be,O
+induced,O
+at,O
+other,O
+stages,O
+of,O
+placental,O
+development,O
+,,O
+we,O
+examined,O
+earlier,O
+placental,O
+specimens,O
+using,O
+a,O
+cell,O
+-,O
+hybridization,O
+assay,O
+.,O
+ , 
+We,O
+found,O
+that,O
+global,O
+X,O
+reactivation,O
+is,O
+also,O
+inducible,O
+in,O
+villi,O
+cells,O
+from,O
+first,O
+-,O
+trimester,O
+spontaneous,O
+abortions,O
+but,O
+not,O
+from,O
+first,O
+-,O
+trimester,O
+elective,O
+terminations,O
+.,O
+ , 
+These,O
+differences,O
+in,O
+inducibility,O
+are,O
+not,O
+associated,O
+with,O
+detectable,O
+variation,O
+in,O
+histone,O
+H4,O
+acetylation,O
+,,O
+DNA,O
+methylation,O
+,,O
+or,O
+XIST,O
+expression,O
+--,O
+hallmarks,O
+of,O
+the,O
+inactivation,O
+process,O
+--,O
+so,O
+other,O
+factors,O
+must,O
+have,O
+a,O
+role,O
+.,O
+ , 
+One,O
+notable,O
+feature,O
+is,O
+that,O
+the,O
+permissive,O
+cells,O
+,,O
+unlike,O
+nonpermissive,O
+ones,O
+,,O
+have,O
+ceased,O
+to,O
+proliferate,O
+in,O
+vivo,O
+and,O
+are,O
+either,O
+beginning,O
+or,O
+in,O
+the,O
+process,O
+of,O
+programmed,O
+cell,O
+death,O
+.,O
+ , 
+Cessation,O
+of,O
+mitotic,O
+proliferation,O
+also,O
+characterizes,O
+oocytes,O
+at,O
+the,O
+stage,O
+at,O
+which,O
+they,O
+undergo,O
+X,O
+reactivation,O
+.,O
+ , 
+We,O
+suggest,O
+that,O
+,,O
+along,O
+with,O
+undermethylation,O
+,,O
+the,O
+apoptotic,O
+changes,O
+accompanying,O
+cessation,O
+of,O
+cell,O
+proliferation,O
+contribute,O
+to,O
+the,O
+reversal,O
+of,O
+inactivation,O
+,,O
+not,O
+only,O
+in,O
+placental,O
+cells,O
+,,O
+but,O
+also,O
+in,O
+oocytes,O
+entering,O
+meiosis,O
+.,O
+ , 
+#9042931
+Detecting,O
+disease,O
+-,O
+predisposing,O
+variants,O
+:,O
+the,O
+haplotype,O
+method,O
+.,O
+ , 
+For,O
+many,O
+HLA,O
+-,O
+associated,O
+diseases,O
+,,O
+multiple,O
+alleles--,O
+and,O
+,,O
+in,O
+some,O
+cases,O
+,,O
+multiple,O
+loci,O
+--,O
+have,O
+been,O
+suggested,O
+as,O
+the,O
+causative,O
+agents,O
+.,O
+ , 
+The,O
+haplotype,O
+method,O
+for,O
+identifying,O
+disease,O
+-,O
+predisposing,O
+amino,O
+acids,O
+in,O
+a,O
+genetic,O
+region,O
+is,O
+a,O
+stratification,O
+analysis,O
+.,O
+ , 
+We,O
+show,O
+that,O
+,,O
+for,O
+each,O
+haplotype,O
+combination,O
+containing,O
+all,O
+the,O
+amino,O
+acid,O
+sites,O
+involved,O
+in,O
+the,O
+disease,O
+process,O
+,,O
+the,O
+relative,O
+frequencies,O
+of,O
+amino,O
+acid,O
+variants,O
+at,O
+sites,O
+not,O
+involved,O
+in,O
+disease,O
+but,O
+in,O
+linkage,O
+disequilibrium,O
+with,O
+the,O
+disease,O
+-,O
+predisposing,O
+sites,O
+are,O
+expected,O
+to,O
+be,O
+the,O
+same,O
+in,O
+patients,O
+and,O
+controls,O
+.,O
+ , 
+The,O
+haplotype,O
+method,O
+is,O
+robust,O
+to,O
+mode,O
+of,O
+inheritance,O
+and,O
+penetrance,O
+of,O
+the,O
+disease,O
+and,O
+can,O
+be,O
+used,O
+to,O
+determine,O
+unequivocally,O
+whether,O
+all,O
+amino,O
+acid,O
+sites,O
+involved,O
+in,O
+the,O
+disease,O
+have,O
+not,O
+been,O
+identified,O
+.,O
+ , 
+Using,O
+a,O
+resampling,O
+technique,O
+,,O
+we,O
+developed,O
+a,O
+statistical,O
+test,O
+that,O
+takes,O
+account,O
+of,O
+the,O
+nonindependence,O
+of,O
+the,O
+sites,O
+sampled,O
+.,O
+ , 
+Further,O
+,,O
+when,O
+multiple,O
+sites,O
+in,O
+the,O
+genetic,O
+region,O
+are,O
+involved,O
+in,O
+disease,O
+,,O
+the,O
+test,O
+statistic,O
+gives,O
+a,O
+closer,O
+fit,O
+to,O
+the,O
+null,O
+expectation,O
+when,O
+some,O
+--,O
+compared,O
+with,O
+none,O
+--,O
+of,O
+the,O
+true,O
+predisposing,O
+factors,O
+are,O
+included,O
+in,O
+the,O
+haplotype,O
+analysis,O
+.,O
+ , 
+Although,O
+the,O
+haplotype,O
+method,O
+can,O
+not,O
+distinguish,O
+between,O
+very,O
+highly,O
+correlated,O
+sites,O
+in,O
+one,O
+population,O
+,,O
+ethnic,O
+comparisons,O
+may,O
+help,O
+identify,O
+the,O
+true,O
+predisposing,O
+factors,O
+.,O
+ , 
+The,O
+haplotype,O
+method,O
+was,O
+applied,O
+to,O
+insulin,O
+-,O
+dependent,O
+diabetes,O
+mellitus,O
+(,O
+IDDM,O
+),O
+HLA,O
+class,O
+II,O
+DQA1,O
+-,O
+DQB1,O
+data,O
+from,O
+Caucasian,O
+,,O
+African,O
+,,O
+and,O
+Japanese,O
+populations,O
+.,O
+ , 
+Our,O
+results,O
+indicate,O
+that,O
+the,O
+combination,O
+DQA1#52,B-Gene
+(,O
+Arg,O
+predisposing,O
+),O
+DQB1#57,B-Gene
+(,O
+Asp,O
+protective,O
+),O
+,,O
+which,O
+has,O
+been,O
+proposed,O
+as,O
+an,O
+important,O
+IDDM,O
+agent,O
+,,O
+does,O
+not,O
+include,O
+all,O
+the,O
+predisposing,O
+elements,O
+.,O
+ , 
+With,O
+rheumatoid,O
+arthritis,O
+HLA,O
+class,O
+II,O
+DRB1,B-Gene
+data,O
+,,O
+the,O
+results,O
+were,O
+consistent,O
+with,O
+the,O
+shared,O
+-,O
+epitope,O
+hypothesis,O
+.,O
+ , 
+#21035103
+Fibrochondrogenesis,O
+results,O
+from,O
+mutations,O
+in,O
+the,O
+COL11A1,B-Gene
+type,O
+XI,O
+collagen,O
+gene,O
+.,O
+ , 
+Fibrochondrogenesis,O
+is,O
+a,O
+severe,O
+,,O
+autosomal,O
+-,O
+recessive,O
+,,O
+short,O
+-,O
+limbed,O
+skeletal,O
+dysplasia,O
+.,O
+ , 
+In,O
+a,O
+single,O
+case,O
+of,O
+fibrochondrogenesis,O
+,,O
+whole,O
+-,O
+genome,O
+SNP,O
+genotyping,O
+identified,O
+unknown,O
+ancestral,O
+consanguinity,O
+by,O
+detecting,O
+three,O
+autozygous,O
+regions,O
+.,O
+ , 
+Because,O
+of,O
+the,O
+predominantly,O
+skeletal,O
+nature,O
+of,O
+the,O
+phenotype,O
+,,O
+the,O
+389,O
+genes,O
+localized,O
+to,O
+the,O
+autozygous,O
+intervals,O
+were,O
+prioritized,O
+for,O
+mutation,O
+analysis,O
+by,O
+correlation,O
+of,O
+their,O
+expression,O
+with,O
+known,O
+cartilage,O
+-,O
+selective,O
+genes,O
+via,O
+the,O
+UCLA,O
+Gene,O
+Expression,O
+Tool,O
+,,O
+UGET,O
+.,O
+ , 
+The,O
+gene,O
+encoding,O
+the,O
+α1,O
+chain,O
+of,O
+type,O
+XI,O
+collagen,O
+(,B-Gene
+COL11A1,I-Gene
+),I-Gene
+was,O
+the,O
+only,O
+cartilage,O
+-,O
+selective,O
+gene,O
+among,O
+the,O
+three,O
+candidate,O
+intervals,O
+.,O
+ , 
+Sequence,O
+analysis,O
+of,O
+COL11A1,B-Gene
+in,O
+two,O
+genetically,O
+independent,O
+fibrochondrogenesis,O
+cases,O
+demonstrated,O
+that,O
+each,O
+was,O
+a,O
+compound,O
+heterozygote,O
+for,O
+a,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutation,O
+on,O
+one,O
+allele,O
+and,O
+a,O
+mutation,O
+predicting,O
+substitution,O
+for,O
+a,O
+conserved,O
+triple,O
+-,O
+helical,O
+glycine,O
+residue,O
+on,O
+the,O
+other,O
+.,O
+ , 
+The,O
+parents,O
+who,O
+were,O
+carriers,O
+of,O
+missense,O
+mutations,O
+had,O
+myopia,O
+.,O
+ , 
+Early,O
+-,O
+onset,O
+hearing,O
+loss,O
+was,O
+noted,O
+in,O
+both,O
+parents,O
+who,O
+carried,O
+a,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+allele,O
+,,O
+suggesting,O
+COL11A1,B-Gene
+as,O
+a,O
+locus,O
+for,O
+mild,O
+,,O
+dominantly,O
+inherited,O
+hearing,O
+loss,O
+.,O
+ , 
+These,O
+findings,O
+identify,O
+COL11A1,B-Gene
+as,O
+a,O
+locus,O
+for,O
+fibrochondrogenesis,O
+and,O
+indicate,O
+that,O
+there,O
+might,O
+be,O
+phenotypic,O
+manifestations,O
+among,O
+carriers,O
+.,O
+ , 
+#11524732
+High,O
+incidence,O
+of,O
+N,B-Gene
+and,O
+K,B-Gene
+-,I-Gene
+Ras,I-Gene
+activating,O
+mutations,O
+in,O
+multiple,O
+myeloma,O
+and,O
+primary,O
+plasma,O
+cell,O
+leukemia,O
+at,O
+diagnosis,O
+.,O
+ , 
+Using,O
+allele,O
+-,O
+specific,O
+amplification,O
+method,O
+(,O
+ARMS,O
+),O
+,,O
+a,O
+highly,O
+sensitive,O
+one,O
+-,O
+stage,O
+allele,O
+-,O
+specific,O
+PCR,O
+,,O
+we,O
+have,O
+evaluated,O
+the,O
+incidence,O
+of,O
+NRAS,O
+and,O
+KRAS2,O
+activating,O
+mutations,O
+(,O
+codons,O
+12,O
+,,O
+13,O
+,,O
+and,O
+61,O
+),O
+in,O
+62,O
+patients,O
+with,O
+either,O
+monoclonal,O
+gammopathy,O
+of,O
+undetermined,O
+significance,O
+(,O
+MGUS,O
+),O
+or,O
+multiple,O
+myeloma,O
+(,O
+MM,O
+),O
+,,O
+primary,O
+plasma,O
+-,O
+cell,O
+leukemia,O
+(,O
+P,O
+-,O
+PCL,O
+),O
+,,O
+and,O
+also,O
+in,O
+human,O
+myeloma,O
+cell,O
+lines,O
+(,O
+HMCL,O
+),O
+.,O
+ , 
+NRAS,B-Gene
+and/or,O
+KRAS2,B-Gene
+mutations,O
+were,O
+found,O
+in,O
+54.5,O
+%,O
+of,O
+MM,O
+at,O
+diagnosis,O
+(,O
+but,O
+in,O
+81,O
+%,O
+at,O
+the,O
+time,O
+of,O
+relapse,O
+),O
+,,O
+in,O
+50,O
+%,O
+of,O
+P,O
+-,O
+PCL,O
+,,O
+and,O
+in,O
+50,O
+%,O
+of,O
+16,O
+HMCL,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+the,O
+occurrence,O
+of,O
+such,O
+mutations,O
+was,O
+very,O
+low,O
+in,O
+MGUS,O
+and,O
+indolent,O
+MM,O
+(,O
+12.50,O
+%,O
+),O
+.,O
+ , 
+Of,O
+note,O
+,,O
+KRAS2,B-Gene
+mutations,O
+were,O
+always,O
+more,O
+frequent,O
+than,O
+NRAS,O
+.,O
+ , 
+The,O
+validity,O
+of,O
+the,O
+technique,O
+was,O
+assessed,O
+by,O
+direct,O
+sequencing,O
+of,O
+cell,O
+lines,O
+and,O
+of,O
+some,O
+patients,O
+.,O
+ , 
+Multiple,O
+mutations,O
+found,O
+in,O
+two,O
+patients,O
+were,O
+confirmed,O
+by,O
+subcloning,O
+exon,O
+PCR,O
+amplification,O
+products,O
+,,O
+testing,O
+clones,O
+with,O
+our,O
+method,O
+,,O
+and,O
+sequencing,O
+them,O
+.,O
+ , 
+Thus,O
+,,O
+these,O
+early,O
+mutations,O
+could,O
+play,O
+a,O
+major,O
+role,O
+in,O
+the,O
+oncogenesis,O
+of,O
+MM,O
+and,O
+P,O
+-,O
+PCL,O
+.,O
+ , 
+#7902670
+Homozygotes,O
+for,O
+the,O
+autosomal,O
+dominant,O
+neoplasia,O
+syndrome,O
+(,B-Gene
+MEN1,I-Gene
+),I-Gene
+.,O
+ , 
+Families,O
+in,O
+which,O
+both,O
+parents,O
+are,O
+heterozygotes,O
+for,O
+the,O
+same,O
+autosomal,O
+dominant,O
+neoplasia,O
+syndrome,O
+are,O
+extremely,O
+unusual,O
+.,O
+ , 
+Recently,O
+,,O
+we,O
+had,O
+the,O
+unique,O
+opportunity,O
+to,O
+evaluate,O
+three,O
+symptomatic,O
+siblings,O
+from,O
+the,O
+union,O
+between,O
+two,O
+unrelated,O
+individuals,O
+affected,O
+by,O
+multiple,O
+endocrine,O
+neoplasia,O
+type,O
+1,O
+(,B-Gene
+MEN1,I-Gene
+),I-Gene
+.,O
+ , 
+When,O
+the,O
+three,O
+siblings,O
+and,O
+their,O
+parents,O
+and,O
+relatives,O
+were,O
+genotyped,O
+for,O
+12,O
+markers,O
+tightly,O
+linked,O
+to,O
+the,O
+MEN1,B-Gene
+locus,O
+,,O
+at,O
+11q13,O
+,,O
+two,O
+of,O
+the,O
+siblings,O
+were,O
+found,O
+to,O
+be,O
+homozygotes,O
+,,O
+and,O
+one,O
+a,O
+heterozygote,O
+,,O
+for,O
+MEN1,B-Gene
+.,I-Gene
+ , 
+With,O
+regard,O
+to,O
+the,O
+MEN1,B-Gene
+syndrome,O
+,,O
+no,O
+phenotypic,O
+differences,O
+were,O
+observed,O
+between,O
+the,O
+two,O
+homozygotes,O
+and,O
+the,O
+heterozygotes,O
+.,O
+ , 
+However,O
+,,O
+the,O
+two,O
+homozygotes,O
+showed,O
+unexplained,O
+infertility,O
+,,O
+which,O
+was,O
+not,O
+the,O
+case,O
+for,O
+any,O
+of,O
+the,O
+heterozygotes,O
+.,O
+ , 
+Thus,O
+,,O
+MEN1,B-Gene
+appears,O
+to,O
+be,O
+a,O
+disease,O
+with,O
+complete,O
+dominance,O
+,,O
+and,O
+the,O
+presence,O
+of,O
+two,O
+MEN1,B-Gene
+alleles,O
+with,O
+mutations,O
+of,O
+the,O
+type,O
+that,O
+occur,O
+constitutionally,O
+may,O
+be,O
+insufficient,O
+for,O
+tumor,O
+development,O
+.,O
+ , 
+#11254449
+HPC2,B-Gene
+variants,O
+and,O
+screen,O
+-,O
+detected,O
+prostate,O
+cancer,O
+.,O
+ , 
+Two,O
+studies,O
+have,O
+reported,O
+significant,O
+associations,O
+between,O
+susceptibility,O
+to,O
+prostate,O
+cancer,O
+and,O
+two,O
+common,O
+missense,O
+variants,O
+of,O
+the,O
+HPC2,B-Gene
+/,B-Gene
+ELAC2,I-Gene
+gene,O
+,,O
+with,O
+estimated,O
+relative,O
+risks,O
+in,O
+the,O
+range,O
+of,O
+two-,O
+to,O
+threefold,O
+.,O
+ , 
+We,O
+investigated,O
+whether,O
+these,O
+polymorphisms,O
+could,O
+be,O
+informative,O
+in,O
+the,O
+prediction,O
+of,O
+the,O
+presence,O
+of,O
+prostate,O
+cancer,O
+in,O
+men,O
+undergoing,O
+prostatic,O
+biopsy,O
+for,O
+the,O
+evaluation,O
+of,O
+an,O
+elevated,O
+serum,O
+-,O
+PSA,O
+level,O
+(,O
+>,O
+or,O
+=,O
+4.0,O
+ng,O
+/,O
+ml,O
+),O
+.,O
+ , 
+We,O
+genotyped,O
+944,O
+men,O
+who,O
+underwent,O
+a,O
+prostate,O
+biopsy,O
+at,O
+our,O
+institution,O
+,,O
+as,O
+well,O
+as,O
+a,O
+control,O
+population,O
+of,O
+922,O
+healthy,O
+,,O
+unselected,O
+women,O
+from,O
+the,O
+same,O
+population,O
+.,O
+ , 
+The,O
+prevalence,O
+of,O
+the,O
+HPC2,B-Gene
+Ala541Thr,B-SNP
+allele,O
+was,O
+similar,O
+in,O
+men,O
+with,O
+prostate,O
+cancer,O
+(,O
+6.3,O
+%,O
+),O
+,,O
+men,O
+with,O
+other,O
+prostatic,O
+conditions,O
+(,O
+6.8,O
+%,O
+),O
+,,O
+and,O
+healthy,O
+women,O
+(,O
+6.3,O
+%,O
+),O
+(,O
+P,O
+=,O
+.83,O
+),O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+HPC2,B-Gene
+genotyping,O
+is,O
+unlikely,O
+to,O
+be,O
+a,O
+useful,O
+adjunct,O
+to,O
+PSA,O
+in,O
+the,O
+prediction,O
+of,O
+the,O
+presence,O
+of,O
+biopsy,O
+-,O
+detected,O
+prostate,O
+cancer,O
+in,O
+asymptomatic,O
+men,O
+.,O
+ , 
+#10090486
+Beta,O
+-,O
+thalassemia,O
+in,O
+the,O
+German,O
+population,O
+:,O
+mediterranean,O
+,,O
+Asian,O
+and,O
+novel,O
+mutations,O
+.,O
+ , 
+Mutations,O
+in,O
+brief,O
+no.228,O
+.,O
+ , 
+Online,O
+.,O
+ , 
+The,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+of,O
+13,O
+unrelated,O
+heterozygous,O
+Germans,O
+who,O
+remained,O
+unidentified,O
+in,O
+a,O
+previous,O
+study,O
+of,O
+40,O
+subjects,O
+were,O
+investigated,O
+at,O
+the,O
+DNA,O
+level,O
+.,O
+ , 
+Two,O
+Mediterranean,O
+,,O
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+Asian,O
+and,O
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+novel,O
+mutations,O
+(,B-SNP
+CD6,I-SNP
+-G,I-SNP
+,,I-SNP
+CDs,B-SNP
+108,I-SNP
+/112,I-SNP
+-,I-SNP
+12nt,I-SNP
+,,I-SNP
+CDs,B-SNP
+130/131,I-SNP
++,I-SNP
+GCCT,I-SNP
+),I-SNP
+were,O
+identified,O
+.,O
+ , 
+Altogether,O
+,,O
+in,O
+30,O
+of,O
+the,O
+35,O
+subjects,O
+(,O
+86,O
+%,O
+),O
+in,O
+which,O
+a,O
+mutation,O
+in,O
+the,O
+beta,B-Gene
+-,I-Gene
+globin,I-Gene
+gene,O
+was,O
+identified,O
+,,O
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+mutation,O
+was,O
+of,O
+Mediterranean,O
+origin,O
+.,O
+ , 
+The,O
+geographical,O
+distribution,O
+suggests,O
+recent,O
+migration,O
+from,O
+the,O
+Mediterranean,O
+region,O
+as,O
+cause,O
+of,O
+the,O
+high,O
+proportion,O
+of,O
+frequent,O
+Mediterranean,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+in,O
+the,O
+German,O
+population,O
+.,O
+ , 
+Our,O
+results,O
+support,O
+the,O
+notion,O
+that,O
+the,O
+majority,O
+of,O
+beta,O
+-,O
+thalassemia,O
+genes,O
+in,O
+the,O
+western,O
+and,O
+central,O
+European,O
+population,O
+are,O
+of,O
+Mediterranean,O
+origin,O
+.,O
+ , 
+#12596792
+Simulation,O
+-,O
+based,O
+P,O
+values,O
+:,O
+response,O
+to,O
+North,O
+et,O
+al,O
+.,O
+ , 
+#8387722
+A,O
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+the,O
+human,O
+haptoglobin,B-Gene
+2,I-Gene
+-,I-Gene
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+modified,O
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+responsiveness,O
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+interleukin-6,B-Gene
+in,O
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+cells,O
+.,O
+ , 
+An,O
+A,B-SNP
+-,I-SNP
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+-,I-SNP
+C,I-SNP
+base,I-SNP
+substitution,I-SNP
+at,I-SNP
+nucleotide,I-SNP
+position,I-SNP
+-61,I-SNP
+in,O
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+promoter,O
+region,O
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+the,O
+human,O
+haptoglobin,B-Gene
+gene,O
+(,B-Gene
+Hp,I-Gene
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+shown,O
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+be,O
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+with,O
+the,O
+haptoglobin,B-Gene
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+1,I-Gene
+modified,O
+(,O
+Hp2,O
+-,O
+1mod,O
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+phenotype,O
+.,O
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+In,O
+order,O
+to,O
+investigate,O
+whether,O
+this,O
+base,O
+substitution,O
+is,O
+the,O
+cause,O
+of,O
+reduced,O
+expression,O
+of,O
+the,O
+Hp2,B-Gene
+allele,O
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+to,O
+the,O
+Hp1,B-Gene
+allele,O
+in,O
+individuals,O
+with,O
+the,O
+Hp2,O
+-,O
+1mod,O
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+,,O
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+the,O
+chloramphenicol,O
+acetyl,O
+transferase,O
+(,O
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+),O
+expression,O
+system,O
+to,O
+evaluate,O
+promoter,O
+function,O
+.,O
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+In,O
+HepG2,O
+cells,O
+,,O
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+normally,O
+express,O
+their,O
+endogenous,O
+haptoglobin,O
+genes,O
+,,O
+CAT,O
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+with,O
+the,O
+-61C,O
+base,O
+change,O
+in,O
+the,O
+promoter,O
+had,O
+about,O
+10,O
+-,O
+fold,O
+-,O
+lower,O
+transcriptional,O
+activity,O
+after,O
+transfection,O
+than,O
+did,O
+the,O
+Hp,O
+control,O
+construct,O
+.,O
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+The,O
+-61C,O
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+also,O
+rendered,O
+the,O
+construct,O
+unresponsive,O
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+treatment,O
+by,O
+interleukin-6,O
+after,O
+transfection,O
+into,O
+Hep3B2,O
+cells,O
+,,O
+which,O
+normally,O
+do,O
+not,O
+express,O
+haptoglobin,O
+but,O
+do,O
+so,O
+in,O
+response,O
+to,O
+stimulation,O
+by,O
+acute,O
+-,O
+phase,O
+reactants,O
+.,O
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+In,O
+addition,O
+,,O
+two,O
+base,O
+substitutions,O
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+T,B-SNP
+to,I-SNP
+A,I-SNP
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+A,I-SNP
+to,I-SNP
+G,I-SNP
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+-104,I-SNP
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+-55,I-SNP
+G,I-SNP
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+promoter,O
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+of,O
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+Hp1,B-Gene
+allele,O
+,,O
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+associated,O
+with,O
+the,O
+Hp2,O
+-,O
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+.,O
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+CAT,O
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+both,O
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+(,B-SNP
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+one,O
+substitution,O
+(,O
+-55,O
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+activity,O
+similar,O
+to,O
+that,O
+in,O
+the,O
+Hp,O
+control,O
+when,O
+transfected,O
+into,O
+both,O
+HepG2,O
+and,O
+Hep3B2,O
+cells,O
+,,O
+although,O
+interleukin-6,B-Gene
+induction,O
+was,O
+less,O
+than,O
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+the,O
+Hp,O
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+construct,O
+.,O
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+These,O
+results,O
+further,O
+support,O
+the,O
+hypothesis,O
+that,O
+the,O
+Hp2,O
+-,O
+1mod,O
+phenotype,O
+results,O
+,,O
+in,O
+part,O
+,,O
+from,O
+the,O
+-61C,O
+mutation,O
+in,O
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+promoter,O
+region,O
+of,O
+the,O
+Hp2,B-Gene
+gene,O
+.,O
+ , 
+#7847368
+Response,O
+to,O
+treatment,O
+in,O
+hereditary,O
+metabolic,O
+disease,O
+:,O
+1993,O
+survey,O
+and,O
+10,O
+-,O
+year,O
+comparison,O
+.,O
+ , 
+Knowledge,O
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+cause,O
+,,O
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+,,O
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+manifestations,O
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+hereditary,O
+metabolic,O
+diseases,O
+puts,O
+them,O
+among,O
+the,O
+best,O
+known,O
+of,O
+all,O
+human,O
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+.,O
+ , 
+On,O
+the,O
+other,O
+hand,O
+,,O
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+of,O
+treatment,O
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+cause,O
+for,O
+uncertainty,O
+and,O
+concern,O
+.,O
+ , 
+In,O
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+,,O
+Hayes,O
+et,O
+al,O
+.,O
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+efficacy,O
+of,O
+treatment,O
+up,O
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+1983,O
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+65,O
+of,O
+these,O
+diseases,O
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+the,O
+McKusick,O
+catalogs,O
+.,O
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+Disease,O
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+calculated,O
+for,O
+seven,O
+parameters,O
+:,O
+longevity,O
+;,O
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+capability,O
+;,O
+somatic,O
+and,O
+cognitive,O
+development,O
+;,O
+and,O
+handicaps,O
+affecting,O
+schooling,O
+,,O
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+,,O
+and,O
+cosmetic,O
+appearance,O
+.,O
+ , 
+Scores,O
+of,O
+the,O
+untreated,O
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+treated,O
+phenotypes,O
+were,O
+then,O
+compared,O
+.,O
+ , 
+We,O
+have,O
+now,O
+measured,O
+progress,O
+over,O
+the,O
+past,O
+decade,O
+by,O
+calculating,O
+scores,O
+on,O
+the,O
+same,O
+65,O
+diseases,O
+from,O
+data,O
+in,O
+several,O
+hundred,O
+new,O
+reports,O
+published,O
+since,O
+1983,O
+.,O
+ , 
+All,O
+seven,O
+parameters,O
+in,O
+the,O
+1993,O
+survey,O
+reflect,O
+improved,O
+efficacy,O
+of,O
+treatment,O
+in,O
+the,O
+10,O
+-,O
+year,O
+interval,O
+.,O
+ , 
+However,O
+,,O
+the,O
+percent,O
+of,O
+diseases,O
+for,O
+which,O
+all,O
+manifestations,O
+of,O
+the,O
+disease,O
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+removed,O
+by,O
+treatment,O
+has,O
+not,O
+changed,O
+(,O
+12,O
+%,O
+in,O
+1983,O
+;,O
+12,O
+%,O
+in,O
+1993,O
+),O
+.,O
+ , 
+The,O
+group,O
+in,O
+which,O
+manifestations,O
+were,O
+untouched,O
+by,O
+treatment,O
+has,O
+become,O
+smaller,O
+(,O
+48,O
+%,O
+in,O
+1983,O
+;,O
+31,O
+%,O
+in,O
+1993,O
+),O
+,,O
+and,O
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+group,O
+partially,O
+ameliorated,O
+by,O
+treatment,O
+had,O
+increased,O
+reciprocally,O
+(,O
+40,O
+%,O
+in,O
+1983,O
+;,O
+57,O
+%,O
+in,O
+1993,O
+),O
+.,O
+ , 
+Progress,O
+in,O
+the,O
+treatment,O
+of,O
+hereditary,O
+metabolic,O
+disease,O
+is,O
+thus,O
+better,O
+than,O
+it,O
+was,O
+,,O
+but,O
+it,O
+is,O
+still,O
+only,O
+a,O
+partial,O
+success,O
+.,O
+ , 
+The,O
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+are,O
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+to,O
+greater,O
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+organ,O
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+tissue,O
+transplantation,O
+,,O
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+Restoration,O
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+treatment,O
+,,O
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+an,O
+elusive,O
+challenge,O
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+is,O
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+,,O
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+for,O
+research,O
+in,O
+human,O
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+.,O
+ , 
+#18950739
+The,O
+Human,O
+Phenotype,O
+Ontology,O
+:,O
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+for,O
+annotating,O
+and,O
+analyzing,O
+human,O
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+disease,O
+.,O
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+There,O
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+thousands,O
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+diseases,O
+in,O
+humans,O
+,,O
+each,O
+of,O
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+has,O
+a,O
+specific,O
+combination,O
+of,O
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+features,O
+,,O
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+computational,O
+analysis,O
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+phenotypic,O
+data,O
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+hampered,O
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+lack,O
+of,O
+adequate,O
+computational,O
+data,O
+structures,O
+.,O
+ , 
+Therefore,O
+,,O
+we,O
+have,O
+developed,O
+a,O
+Human,O
+Phenotype,O
+Ontology,O
+(,O
+HPO,O
+),O
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+over,O
+8000,O
+terms,O
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+individual,O
+phenotypic,O
+anomalies,O
+and,O
+have,O
+annotated,O
+all,O
+clinical,O
+entries,O
+in,O
+Online,O
+Mendelian,O
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+Man,O
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+terms,O
+of,O
+the,O
+HPO,O
+.,O
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+We,O
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+that,O
+the,O
+HPO,O
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+able,O
+to,O
+capture,O
+phenotypic,O
+similarities,O
+between,O
+diseases,O
+in,O
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+useful,O
+and,O
+highly,O
+significant,O
+fashion,O
+.,O
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+#22226083
+Transient,O
+infantile,O
+hypertriglyceridemia,O
+,,O
+fatty,O
+liver,O
+,,O
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+hepatic,O
+fibrosis,O
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+by,O
+mutated,O
+GPD1,B-Gene
+,,I-Gene
+encoding,O
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+ , 
+The,O
+molecular,O
+basis,O
+for,O
+primary,O
+hereditary,O
+hypertriglyceridemia,O
+has,O
+been,O
+identified,O
+in,O
+fewer,O
+than,O
+5,O
+%,O
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+.,O
+ , 
+Investigation,O
+of,O
+monogenic,O
+dyslipidemias,O
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+the,O
+potential,O
+to,O
+expose,O
+key,O
+metabolic,O
+pathways,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+hitherto,O
+unreported,O
+disease,O
+in,O
+ten,O
+individuals,O
+manifesting,O
+as,O
+moderate,O
+to,O
+severe,O
+transient,O
+childhood,O
+hypertriglyceridemia,O
+and,O
+fatty,O
+liver,O
+followed,O
+by,O
+hepatic,O
+fibrosis,O
+and,O
+the,O
+identification,O
+of,O
+the,O
+mutated,O
+gene,O
+responsible,O
+for,O
+this,O
+condition,O
+.,O
+ , 
+We,O
+performed,O
+SNP,O
+array,O
+-,O
+based,O
+homozygosity,O
+mapping,O
+and,O
+found,O
+a,O
+single,O
+large,O
+continuous,O
+segment,O
+of,O
+homozygosity,O
+on,O
+chromosomal,O
+region,O
+12q13.12,O
+.,O
+ , 
+The,O
+candidate,O
+region,O
+contained,O
+35,O
+genes,O
+that,O
+are,O
+listed,O
+in,O
+Online,O
+Mendelian,O
+Inheritance,O
+in,O
+Man,O
+(,O
+OMIM,O
+),O
+and,O
+27,O
+other,O
+genes,O
+.,O
+ , 
+We,O
+performed,O
+candidate,O
+gene,O
+sequencing,O
+and,O
+screened,O
+both,O
+clinically,O
+affected,O
+individuals,O
+(,O
+children,O
+and,O
+adults,O
+with,O
+hypertriglyceridemia,O
+),O
+and,O
+also,O
+a,O
+healthy,O
+cohort,O
+for,O
+mutations,O
+in,O
+GPD1,B-Gene
+,,I-Gene
+which,O
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+glycerol-3,B-Gene
+-,I-Gene
+phosphate,I-Gene
+dehydrogenase,I-Gene
+1,I-Gene
+.,I-Gene
+ , 
+Mutation,O
+analysis,O
+revealed,O
+a,O
+homozygous,O
+splicing,O
+mutation,O
+,,O
+c.361,B-SNP
+-,I-SNP
+1G,I-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+which,O
+resulted,O
+in,O
+an,O
+aberrantly,O
+spliced,O
+mRNA,O
+in,O
+the,O
+ten,O
+affected,O
+individuals,O
+.,O
+ , 
+This,O
+mutation,O
+is,O
+predicted,O
+to,O
+result,O
+in,O
+a,O
+truncated,O
+protein,O
+lacking,O
+essential,O
+conserved,O
+residues,O
+,,O
+including,O
+a,O
+functional,O
+site,O
+responsible,O
+for,O
+initial,O
+substrate,O
+recognition,O
+.,O
+ , 
+Functional,O
+consequences,O
+of,O
+the,O
+mutation,O
+were,O
+evaluated,O
+by,O
+measuring,O
+intracellular,O
+concentrations,O
+of,O
+cholesterol,O
+and,O
+triglyceride,O
+as,O
+well,O
+as,O
+triglyceride,O
+secretion,O
+in,O
+HepG2,O
+(,O
+hepatocellular,O
+carcinoma,O
+),O
+human,O
+cells,O
+lines,O
+overexpressing,O
+normal,O
+and,O
+mutant,O
+GPD1,B-Gene
+cDNA,O
+.,O
+ , 
+Overexpression,O
+of,O
+mutant,O
+GPD1,B-Gene
+in,O
+HepG2,O
+cells,O
+,,O
+in,O
+comparison,O
+to,O
+overexpression,O
+of,O
+wild,O
+-,O
+type,O
+GPD1,B-Gene
+,,I-Gene
+resulted,O
+in,O
+increased,O
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+of,O
+triglycerides,O
+(,O
+p,O
+=,O
+0.01,O
+),O
+.,O
+ , 
+This,O
+finding,O
+supports,O
+the,O
+pathogenicity,O
+of,O
+the,O
+identified,O
+mutation,O
+.,O
+ , 
+#1284534
+Mutations,O
+and,O
+sequence,O
+variations,O
+detected,O
+in,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+transmembrane,I-Gene
+conductance,I-Gene
+regulator,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+:,O
+a,O
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+from,O
+the,O
+Cystic,O
+Fibrosis,O
+Genetic,O
+Analysis,O
+Consortium,O
+.,O
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+Cystic,O
+fibrosis,O
+is,O
+the,O
+most,O
+common,O
+autosomal,O
+disorder,O
+in,O
+the,O
+Caucasian,O
+population,O
+.,O
+ , 
+Since,O
+the,O
+description,O
+of,O
+the,O
+major,O
+mutation,O
+of,O
+this,O
+disease,O
+in,O
+1989,O
+,,O
+over,O
+150,O
+of,O
+additional,O
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+the,O
+CFTR,O
+gene,O
+.,O
+ , 
+This,O
+update,O
+summarizes,O
+the,O
+different,O
+mutations,O
+identified,O
+and,O
+reported,O
+before,O
+March,O
+15,O
+by,O
+members,O
+of,O
+the,O
+international,O
+Cystic,O
+Fibrosis,O
+Genetic,O
+Analysis,O
+Consortium,O
+.,O
+ , 
+The,O
+report,O
+includes,O
+information,O
+on,O
+DNA,O
+sequence,O
+variations,O
+found,O
+in,O
+the,O
+gene,O
+.,O
+ , 
+#8037216
+Comparison,O
+of,O
+statistics,O
+for,O
+candidate,O
+-,O
+gene,O
+association,O
+studies,O
+using,O
+cases,O
+and,O
+parents,O
+.,O
+ , 
+Studies,O
+of,O
+association,O
+between,O
+candidate,O
+genes,O
+and,O
+disease,O
+can,O
+be,O
+designed,O
+to,O
+use,O
+cases,O
+with,O
+disease,O
+,,O
+and,O
+in,O
+place,O
+of,O
+nonrelated,O
+controls,O
+,,O
+their,O
+parents,O
+.,O
+ , 
+The,O
+advantage,O
+of,O
+this,O
+design,O
+is,O
+the,O
+elimination,O
+of,O
+spurious,O
+differences,O
+due,O
+to,O
+ethnic,O
+differences,O
+between,O
+cases,O
+and,O
+nonrelated,O
+controls,O
+.,O
+ , 
+However,O
+,,O
+several,O
+statistical,O
+methods,O
+of,O
+analysis,O
+have,O
+been,O
+proposed,O
+in,O
+the,O
+literature,O
+,,O
+and,O
+the,O
+choice,O
+of,O
+analysis,O
+is,O
+not,O
+always,O
+clear,O
+.,O
+ , 
+We,O
+review,O
+some,O
+of,O
+the,O
+statistical,O
+methods,O
+currently,O
+developed,O
+and,O
+present,O
+two,O
+new,O
+statistical,O
+methods,O
+aimed,O
+at,O
+specific,O
+genetic,O
+hypotheses,O
+of,O
+dominance,O
+and,O
+recessivity,O
+of,O
+the,O
+candidate,O
+gene,O
+.,O
+ , 
+These,O
+new,O
+methods,O
+can,O
+be,O
+more,O
+powerful,O
+than,O
+other,O
+current,O
+methods,O
+,,O
+as,O
+demonstrated,O
+by,O
+simulations,O
+.,O
+ , 
+The,O
+basis,O
+of,O
+these,O
+new,O
+statistical,O
+methods,O
+is,O
+a,O
+likelihood,O
+approach,O
+.,O
+ , 
+The,O
+advantage,O
+of,O
+the,O
+likelihood,O
+framework,O
+is,O
+that,O
+regression,O
+models,O
+can,O
+be,O
+developed,O
+to,O
+assess,O
+genotype,O
+-,O
+environment,O
+interactions,O
+,,O
+as,O
+well,O
+as,O
+the,O
+relative,O
+contribution,O
+that,O
+alleles,O
+at,O
+the,O
+candidate,O
+-,O
+gene,O
+locus,O
+make,O
+to,O
+the,O
+relative,O
+risk,O
+(,O
+RR,O
+),O
+of,O
+disease,O
+.,O
+ , 
+This,O
+latter,O
+development,O
+allows,O
+testing,O
+of,O
+(,O
+1,O
+),O
+whether,O
+interactions,O
+between,O
+alleles,O
+exist,O
+,,O
+on,O
+the,O
+scale,O
+of,O
+log,O
+RR,O
+,,O
+and,O
+(,O
+2,O
+),O
+whether,O
+alleles,O
+originating,O
+from,O
+the,O
+mother,O
+or,O
+father,O
+of,O
+a,O
+case,O
+impart,O
+different,O
+risks,O
+,,O
+i.e.,O
+,,O
+genomic,O
+imprinting,O
+.,O
+ , 
+#11524734
+Identification,O
+of,O
+seven,O
+novel,O
+mutations,O
+including,O
+the,O
+first,O
+two,O
+genomic,O
+rearrangements,O
+in,O
+SLC26A3,B-Gene
+mutated,O
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+congenital,O
+chloride,O
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+Congenital,O
+chloride,O
+diarrhea,O
+(,O
+CLD,O
+),O
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+an,O
+autosomal,O
+recessive,O
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+characterized,O
+by,O
+defective,O
+intestinal,O
+electrolyte,O
+absorption,O
+,,O
+resulting,O
+in,O
+voluminous,O
+osmotic,O
+diarrhea,O
+with,O
+high,O
+chloride,O
+content,O
+.,O
+ , 
+A,O
+variety,O
+of,O
+mutations,O
+in,O
+the,O
+solute,B-Gene
+carrier,I-Gene
+family,I-Gene
+26,I-Gene
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+SLC26A3,I-Gene
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+known,O
+as,O
+CLD,B-Gene
+or,O
+DRA,B-Gene
+),I-Gene
+are,O
+responsible,O
+for,O
+the,O
+disease,O
+.,O
+ , 
+Since,O
+the,O
+identification,O
+of,O
+the,O
+SLC26A3,O
+gene,O
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+the,O
+determination,O
+of,O
+its,O
+genomic,O
+structure,O
+,,O
+altogether,O
+three,O
+founder,O
+and,O
+17,O
+private,O
+mutations,O
+have,O
+been,O
+characterized,O
+within,O
+miscellaneous,O
+ethnic,O
+groups,O
+.,O
+ , 
+We,O
+screened,O
+for,O
+mutations,O
+in,O
+seven,O
+unrelated,O
+families,O
+with,O
+CLD,O
+.,O
+ , 
+The,O
+diagnoses,O
+were,O
+confirmed,O
+by,O
+fecal,O
+chloride,O
+measurements,O
+.,O
+ , 
+The,O
+combined,O
+PCR,O
+-,O
+SSCP,O
+and,O
+sequencing,O
+analyses,O
+revealed,O
+altogether,O
+seven,O
+novel,O
+mutations,O
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+two,O
+missense,O
+mutations,O
+(,B-SNP
+S206P,I-SNP
+,,I-SNP
+D468V,B-SNP
+),I-SNP
+,,O
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+defects,O
+(,B-SNP
+IVS12,I-SNP
+-,I-SNP
+1G,I-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+IVS13,B-SNP
+-,I-SNP
+2delA,I-SNP
+),I-SNP
+,,O
+one,O
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+mutation,O
+(,B-SNP
+Q436X,I-SNP
+),I-SNP
+,,O
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+insertion,O
+/,O
+deletion,O
+mutation,O
+(,B-SNP
+2104,I-SNP
+-,I-SNP
+2105delGGins29,I-SNP
+-,I-SNP
+bp,I-SNP
+),I-SNP
+,,O
+and,O
+an,O
+intragenic,O
+deletion,O
+of,O
+SLC26A3,B-Gene
+exons,O
+7,O
+and,O
+8,O
+.,O
+ , 
+Two,O
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+identified,O
+mutations,O
+were,O
+also,O
+found,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+rearrangement,O
+mutations,O
+in,O
+SLC26A3,B-Gene
+.,I-Gene
+ , 
+Molecular,O
+features,O
+predisposing,O
+SLC26A3,B-Gene
+for,O
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+two,O
+rearrangements,O
+may,O
+include,O
+repetitive,O
+elements,O
+and,O
+palindromic,O
+-,O
+like,O
+sequences,O
+.,O
+ , 
+The,O
+increasingly,O
+wide,O
+diversity,O
+of,O
+SLC26A3,B-Gene
+mutations,O
+suggests,O
+that,O
+mutations,O
+in,O
+the,O
+SLC26A3,B-Gene
+gene,O
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+not,O
+be,O
+rare,O
+events,O
+.,O
+ , 
+#10577916
+Variation,O
+in,O
+short,O
+tandem,O
+repeats,O
+is,O
+deeply,O
+structured,O
+by,O
+genetic,O
+background,O
+on,O
+the,O
+human,O
+Y,O
+chromosome,O
+.,O
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+Eleven,O
+biallelic,O
+polymorphisms,O
+and,O
+seven,O
+short,O
+-,O
+tandem,O
+-,O
+repeat,O
+(,O
+STR,O
+),O
+loci,O
+mapping,O
+on,O
+the,O
+nonrecombining,O
+portion,O
+of,O
+the,O
+human,O
+Y,O
+chromosome,O
+have,O
+been,O
+typed,O
+in,O
+men,O
+from,O
+northwestern,O
+Africa,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+biallelic,O
+markers,O
+,,O
+which,O
+represent,O
+probable,O
+unique,O
+events,O
+in,O
+human,O
+evolution,O
+,,O
+allowed,O
+us,O
+to,O
+characterize,O
+the,O
+stable,O
+backgrounds,O
+or,O
+haplogroups,O
+of,O
+Y,O
+chromosomes,O
+that,O
+prevail,O
+in,O
+this,O
+geographic,O
+region,O
+.,O
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+Variation,O
+in,O
+the,O
+more,O
+rapidly,O
+mutating,O
+genetic,O
+markers,O
+(,O
+STRs,O
+),O
+has,O
+been,O
+used,O
+both,O
+to,O
+estimate,O
+the,O
+time,O
+to,O
+the,O
+most,O
+recent,O
+common,O
+ancestor,O
+for,O
+STR,O
+variability,O
+within,O
+these,O
+stable,O
+backgrounds,O
+and,O
+to,O
+explore,O
+whether,O
+STR,O
+differentiation,O
+among,O
+haplogroups,O
+still,O
+retains,O
+information,O
+about,O
+their,O
+phylogeny,O
+.,O
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+When,O
+analysis,O
+of,O
+molecular,O
+variance,O
+was,O
+used,O
+to,O
+study,O
+the,O
+apportionment,O
+of,O
+STR,O
+variation,O
+among,O
+both,O
+genetic,O
+backgrounds,O
+(,O
+i.e.,O
+,,O
+those,O
+defined,O
+by,O
+haplogroups,O
+),O
+and,O
+population,O
+backgrounds,O
+,,O
+we,O
+found,O
+STR,O
+variability,O
+to,O
+be,O
+clearly,O
+structured,O
+by,O
+haplogroups,O
+.,O
+ , 
+More,O
+than,O
+80,O
+%,O
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+the,O
+genetic,O
+variance,O
+was,O
+found,O
+among,O
+haplogroups,O
+,,O
+whereas,O
+only,O
+3.72,O
+%,O
+of,O
+the,O
+genetic,O
+variation,O
+could,O
+be,O
+attributed,O
+to,O
+differences,O
+among,O
+populations,O
+-,O
+that,O
+is,O
+,,O
+genetic,O
+variability,O
+appears,O
+to,O
+be,O
+much,O
+more,O
+structured,O
+by,O
+lineage,O
+than,O
+by,O
+population,O
+.,O
+ , 
+This,O
+was,O
+confirmed,O
+when,O
+two,O
+population,O
+samples,O
+from,O
+the,O
+Iberian,O
+Peninsula,O
+were,O
+added,O
+to,O
+the,O
+analysis,O
+.,O
+ , 
+The,O
+deep,O
+structure,O
+of,O
+the,O
+genetic,O
+variation,O
+in,O
+old,O
+genealogical,O
+units,O
+(,O
+haplogroups,O
+),O
+challenges,O
+a,O
+population,O
+-,O
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+perspective,O
+in,O
+the,O
+comprehension,O
+of,O
+human,O
+genome,O
+diversity,O
+.,O
+ , 
+A,O
+population,O
+may,O
+be,O
+better,O
+understood,O
+as,O
+an,O
+association,O
+of,O
+lineages,O
+from,O
+a,O
+deep,O
+and,O
+population,O
+-,O
+independent,O
+gene,O
+genealogy,O
+,,O
+rather,O
+than,O
+as,O
+a,O
+complete,O
+evolutionary,O
+unit,O
+.,O
+ , 
+#8503437
+X,O
+-,O
+linked,O
+mental,O
+retardation,O
+:,O
+in,O
+pursuit,O
+of,O
+a,O
+gene,O
+map,O
+.,O
+ , 
+#18521937
+Mutations,O
+in,O
+CNGA3,B-Gene
+impair,O
+trafficking,O
+or,O
+function,O
+of,O
+cone,O
+cyclic,O
+nucleotide,O
+-,O
+gated,O
+channels,O
+,,O
+resulting,O
+in,O
+achromatopsia,O
+.,O
+ , 
+CNGA3,B-Gene
+encodes,O
+the,O
+A,O
+-,O
+subunit,O
+of,O
+the,O
+cone,O
+photoreceptor,O
+cyclic,O
+nucleotide,O
+-,O
+gated,O
+(,O
+CNG,O
+),O
+channel,O
+,,O
+which,O
+is,O
+a,O
+crucial,O
+component,O
+of,O
+the,O
+phototransduction,O
+cascade,O
+in,O
+cone,O
+outer,O
+segments,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+CNGA3,B-Gene
+gene,O
+have,O
+been,O
+associated,O
+with,O
+complete,O
+and,O
+incomplete,O
+forms,O
+of,O
+achromatopsia,O
+(,O
+ACHR,O
+),O
+,,O
+a,O
+congenital,O
+,,O
+autosomal,O
+recessively,O
+inherited,O
+retinal,O
+disorder,O
+characterized,O
+by,O
+lack,O
+of,O
+color,O
+discrimination,O
+,,O
+reduced,O
+visual,O
+acuity,O
+,,O
+nystagmus,O
+,,O
+and,O
+photophobia,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+the,O
+identification,O
+of,O
+three,O
+novel,O
+CNGA3,B-Gene
+missense,O
+mutations,O
+in,O
+ACHR,O
+patients,O
+:,O
+c.682G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+E228,I-SNP
+K,I-SNP
+),I-SNP
+,,O
+c.1315C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+R439W,I-SNP
+),I-SNP
+,,O
+and,O
+c.1405G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+A469,I-SNP
+T,I-SNP
+),I-SNP
+,,O
+and,O
+the,O
+detailed,O
+functional,O
+analyses,O
+of,O
+these,O
+new,O
+as,O
+well,O
+as,O
+five,O
+previously,O
+reported,O
+mutations,O
+(,B-SNP
+R283Q,I-SNP
+,,I-SNP
+T291R,B-SNP
+,,I-SNP
+F547L,B-SNP
+,,I-SNP
+G557R,B-SNP
+,,I-SNP
+and,O
+E590,B-SNP
+K,I-SNP
+),I-SNP
+,,O
+in,O
+conjunction,O
+with,O
+clinical,O
+data,O
+of,O
+patients,O
+carrying,O
+these,O
+mutations,O
+,,O
+to,O
+establish,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+.,O
+ , 
+The,O
+functional,O
+characterization,O
+of,O
+mutant,O
+CNGA3,B-Gene
+channels,O
+was,O
+performed,O
+with,O
+calcium,O
+imaging,O
+and,O
+patch,O
+clamp,O
+recordings,O
+in,O
+a,O
+heterologous,O
+HEK293,O
+cell,O
+expression,O
+system,O
+.,O
+ , 
+Results,O
+were,O
+corroborated,O
+by,O
+immunostaining,O
+and,O
+colocalization,O
+experiments,O
+of,O
+the,O
+channel,O
+protein,O
+with,O
+the,O
+plasma,O
+membrane,O
+.,O
+ , 
+Several,O
+mutations,O
+evoked,O
+pronounced,O
+alterations,O
+of,O
+the,O
+apparent,O
+cGMP,O
+sensitivity,O
+of,O
+mutant,O
+channels,O
+.,O
+ , 
+These,O
+functional,O
+defects,O
+were,O
+fully,O
+or,O
+partially,O
+compensated,O
+by,O
+coexpressing,O
+the,O
+mutant,O
+CNGA3,B-Gene
+subunit,O
+with,O
+the,O
+wild,O
+-,O
+type,O
+CNGB3,B-Gene
+subunit,O
+for,O
+channels,O
+with,O
+the,O
+mutations,O
+R439W,B-SNP
+,,I-SNP
+A469,B-SNP
+T,I-SNP
+,,I-SNP
+F547L,B-SNP
+,,I-SNP
+and,O
+E590,B-SNP
+K.,I-SNP
+We,O
+could,O
+show,O
+that,O
+several,O
+mutant,O
+channels,O
+with,O
+agonist,O
+dose,O
+-,O
+response,O
+relationships,O
+similar,O
+to,O
+the,O
+wild,O
+-,O
+type,O
+exhibited,O
+severely,O
+impaired,O
+membrane,O
+targeting,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+this,O
+study,O
+presents,O
+the,O
+positive,O
+effect,O
+of,O
+reduced,O
+cell,O
+culture,O
+temperature,O
+on,O
+surface,O
+expression,O
+and,O
+functional,O
+performance,O
+of,O
+mutant,O
+CNG,O
+channels,O
+with,O
+protein,O
+folding,O
+or,O
+trafficking,O
+defects,O
+.,O
+ , 
+#15309688
+The,O
+Longue,O
+Durée,O
+of,O
+genetic,O
+ancestry,O
+:,O
+multiple,O
+genetic,O
+marker,O
+systems,O
+and,O
+Celtic,O
+origins,O
+on,O
+the,O
+Atlantic,O
+facade,O
+of,O
+Europe,O
+.,O
+ , 
+Celtic,O
+languages,O
+are,O
+now,O
+spoken,O
+only,O
+on,O
+the,O
+Atlantic,O
+facade,O
+of,O
+Europe,O
+,,O
+mainly,O
+in,O
+Britain,O
+and,O
+Ireland,O
+,,O
+but,O
+were,O
+spoken,O
+more,O
+widely,O
+in,O
+western,O
+and,O
+central,O
+Europe,O
+until,O
+the,O
+collapse,O
+of,O
+the,O
+Roman,O
+Empire,O
+in,O
+the,O
+first,O
+millennium,O
+a.d,O
+.,O
+ , 
+It,O
+has,O
+been,O
+common,O
+to,O
+couple,O
+archaeological,O
+evidence,O
+for,O
+the,O
+expansion,O
+of,O
+Iron,O
+Age,O
+elites,O
+in,O
+central,O
+Europe,O
+with,O
+the,O
+dispersal,O
+of,O
+these,O
+languages,O
+and,O
+of,O
+Celtic,O
+ethnicity,O
+and,O
+to,O
+posit,O
+a,O
+central,O
+European,O
+",O
+homeland,O
+",O
+for,O
+the,O
+Celtic,O
+peoples,O
+.,O
+ , 
+More,O
+recently,O
+,,O
+however,O
+,,O
+archaeologists,O
+have,O
+questioned,O
+this,O
+",O
+migrationist,O
+",O
+view,O
+of,O
+Celtic,O
+ethnogenesis,O
+.,O
+ , 
+The,O
+proposition,O
+of,O
+a,O
+central,O
+European,O
+ancestry,O
+should,O
+be,O
+testable,O
+by,O
+examining,O
+the,O
+distribution,O
+of,O
+genetic,O
+markers,O
+;,O
+however,O
+,,O
+although,O
+Y,O
+-,O
+chromosome,O
+patterns,O
+in,O
+Atlantic,O
+Europe,O
+show,O
+little,O
+evidence,O
+of,O
+central,O
+European,O
+influence,O
+,,O
+there,O
+has,O
+hitherto,O
+been,O
+insufficient,O
+data,O
+to,O
+confirm,O
+this,O
+by,O
+use,O
+of,O
+mitochondrial,O
+DNA,O
+(,O
+mtDNA,O
+),O
+.,O
+ , 
+Here,O
+,,O
+we,O
+present,O
+both,O
+new,O
+mtDNA,O
+data,O
+from,O
+Ireland,O
+and,O
+a,O
+novel,O
+analysis,O
+of,O
+a,O
+greatly,O
+enlarged,O
+European,O
+mtDNA,O
+database,O
+.,O
+ , 
+We,O
+show,O
+that,O
+mtDNA,O
+lineages,O
+,,O
+when,O
+analyzed,O
+in,O
+sufficiently,O
+large,O
+numbers,O
+,,O
+display,O
+patterns,O
+significantly,O
+similar,O
+to,O
+a,O
+large,O
+fraction,O
+of,O
+both,O
+Y,O
+-,O
+chromosome,O
+and,O
+autosomal,O
+variation,O
+.,O
+ , 
+These,O
+multiple,O
+genetic,O
+marker,O
+systems,O
+indicate,O
+a,O
+shared,O
+ancestry,O
+throughout,O
+the,O
+Atlantic,O
+zone,O
+,,O
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+northern,O
+Iberia,O
+to,O
+western,O
+Scandinavia,O
+,,O
+that,O
+dates,O
+back,O
+to,O
+the,O
+end,O
+of,O
+the,O
+last,O
+Ice,O
+Age,O
+.,O
+ , 
+#1301931
+Polymorphic,O
+variation,O
+within,O
+",O
+conserved,O
+",O
+sequences,O
+at,O
+the,O
+3,O
+',O
+end,O
+of,O
+the,O
+human,O
+RDS,B-Gene
+gene,O
+which,O
+results,O
+in,O
+amino,O
+acid,O
+substitutions,O
+.,O
+ , 
+The,O
+human,O
+RDS,B-Gene
+gene,O
+,,O
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+mapped,O
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+chromosome,O
+6p,O
+,,O
+encodes,O
+a,O
+protein,O
+found,O
+in,O
+the,O
+outer,O
+disc,O
+membrane,O
+of,O
+the,O
+photoreceptor,O
+cells,O
+of,O
+the,O
+retina,O
+.,O
+ , 
+The,O
+cDNA,O
+sequence,O
+of,O
+the,O
+human,O
+gene,O
+shows,O
+85,O
+%,O
+identity,O
+with,O
+the,O
+bovine,O
+peripherin,O
+gene,O
+and,O
+the,O
+rds,B-Gene
+(,B-Gene
+retinal,I-Gene
+degeneration,I-Gene
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+genes,O
+from,O
+mouse,O
+and,O
+rat,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+RDS,O
+gene,O
+have,O
+recently,O
+been,O
+implicated,O
+in,O
+autosomal,B-Gene
+dominant,I-Gene
+retinitis,I-Gene
+pigmentosa,I-Gene
+(,B-Gene
+adRP,I-Gene
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+in,O
+some,O
+families,O
+.,O
+ , 
+Here,O
+we,O
+present,O
+evidence,O
+that,O
+the,O
+third,O
+exon,O
+of,O
+this,O
+gene,O
+is,O
+subject,O
+to,O
+polymorphic,O
+variation,O
+in,O
+humans,O
+.,O
+ , 
+The,O
+three,O
+sequence,O
+alterations,O
+described,O
+in,O
+this,O
+paper,O
+give,O
+rise,O
+to,O
+amino,O
+acid,O
+substitutions,O
+.,O
+ , 
+However,O
+,,O
+as,O
+these,O
+missense,O
+mutations,O
+also,O
+occur,O
+in,O
+the,O
+normal,O
+population,O
+they,O
+are,O
+not,O
+implicated,O
+as,O
+causing,O
+adRP,O
+.,O
+ , 
+Interestingly,O
+such,O
+sequence,O
+variation,O
+is,O
+not,O
+found,O
+within,O
+other,O
+species,O
+examined,O
+including,O
+mouse,O
+and,O
+bovine,O
+.,O
+ , 
+These,O
+intragenic,O
+polymorphisms,O
+will,O
+be,O
+of,O
+future,O
+potential,O
+value,O
+in,O
+studies,O
+to,O
+locate,O
+further,O
+disease,O
+causing,O
+mutations,O
+in,O
+adRP,O
+patients,O
+in,O
+the,O
+RDS,B-Gene
+gene,O
+.,O
+ , 
+#7912883
+The,O
+genetics,O
+of,O
+human,O
+limb,O
+development,O
+.,O
+ , 
+#19626718
+Insights,O
+into,O
+the,O
+importance,O
+of,O
+miRNA,O
+-,O
+related,O
+polymorphisms,O
+to,O
+heart,O
+disease,O
+.,O
+ , 
+#8318989
+Screening,O
+for,O
+molecular,O
+pathologies,O
+in,O
+Lesch,O
+-,O
+Nyhan,O
+syndrome,O
+.,O
+ , 
+Heteroduplex,O
+detection,O
+by,O
+hydrolink,O
+gel,O
+electrophoresis,O
+was,O
+performed,O
+to,O
+screen,O
+for,O
+small,O
+mutations,O
+in,O
+12,O
+Lesch,O
+-,O
+Nyhan,O
+syndrome,O
+families,O
+with,O
+characterised,O
+molecular,O
+pathology,O
+which,O
+included,O
+nine,O
+point,O
+mutations,O
+,,O
+two,O
+small,O
+deletions,O
+,,O
+and,O
+a,O
+1,O
+-,O
+bp,O
+insertion,O
+.,O
+ , 
+This,O
+modified,O
+protocol,O
+for,O
+heteroduplex,O
+detection,O
+by,O
+hydrolink,O
+gel,O
+electrophoresis,O
+detected,O
+all,O
+12,O
+of,O
+these,O
+mutations,O
+and,O
+was,O
+utilised,O
+to,O
+rapidly,O
+determine,O
+the,O
+carrier,O
+status,O
+of,O
+females,O
+from,O
+affected,O
+families,O
+.,O
+ , 
+On,O
+the,O
+basis,O
+of,O
+these,O
+results,O
+this,O
+approach,O
+appears,O
+to,O
+be,O
+a,O
+rapid,O
+and,O
+reliable,O
+screening,O
+method,O
+for,O
+point,O
+mutations,O
+in,O
+addition,O
+to,O
+small,O
+length,O
+mutations,O
+and,O
+for,O
+carrier,O
+detection,O
+in,O
+Lesch,O
+-,O
+Nyhan,O
+syndrome,O
+.,O
+ , 
+#21280151
+Searching,O
+for,O
+the,O
+missing,O
+heritability,O
+of,O
+complex,O
+diseases,O
+.,O
+ , 
+#12016592
+Intron,O
+-,O
+size,O
+constraint,O
+as,O
+a,O
+mutational,O
+mechanism,O
+in,O
+Rothmund,O
+-,O
+Thomson,O
+syndrome,O
+.,O
+ , 
+Rothmund,O
+-,O
+Thomson,O
+syndrome,O
+(,O
+RTS,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+caused,O
+by,O
+deleterious,O
+mutations,O
+in,O
+the,O
+RECQL4,B-Gene
+gene,O
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+chromosome,O
+8,O
+.,O
+ , 
+The,O
+RECQL4,B-Gene
+gene,O
+structure,O
+is,O
+unusual,O
+because,O
+it,O
+contains,O
+many,O
+small,O
+introns,O
+<,O
+100,O
+bp,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+proband,O
+with,O
+RTS,O
+who,O
+has,O
+a,O
+novel,O
+11,O
+-,O
+bp,O
+intronic,O
+deletion,O
+,,O
+and,O
+we,O
+show,O
+that,O
+this,O
+mutation,O
+results,O
+in,O
+a,O
+66,O
+-,O
+bp,O
+intron,O
+too,O
+small,O
+for,O
+proper,O
+splicing,O
+.,O
+ , 
+Constraint,O
+on,O
+intron,O
+size,O
+may,O
+represent,O
+a,O
+general,O
+mutational,O
+mechanism,O
+,,O
+since,O
+human,O
+-,O
+genome,O
+analysis,O
+reveals,O
+that,O
+approximately,O
+15,O
+%,O
+of,O
+genes,O
+have,O
+introns,O
+<,O
+100,O
+bp,O
+and,O
+are,O
+therefore,O
+susceptible,O
+to,O
+size,O
+constraint,O
+.,O
+ , 
+Thus,O
+,,O
+monitoring,O
+of,O
+intron,O
+size,O
+may,O
+allow,O
+detection,O
+of,O
+mutations,O
+missed,O
+by,O
+exon,O
+-,O
+by,O
+-,O
+exon,O
+approaches,O
+.,O
+ , 
+#15053010
+2003,O
+Curt,O
+Stern,O
+Award,O
+address,O
+.,O
+ , 
+On,O
+low,O
+expectation,O
+exceeded,O
+;,O
+or,O
+,,O
+the,O
+genomic,O
+salvation,O
+of,O
+the,O
+Y,O
+chromosome,O
+.,O
+ , 
+#21944045
+Denisova,O
+admixture,O
+and,O
+the,O
+first,O
+modern,O
+human,O
+dispersals,O
+into,O
+Southeast,O
+Asia,O
+and,O
+Oceania,O
+.,O
+ , 
+It,O
+has,O
+recently,O
+been,O
+shown,O
+that,O
+ancestors,O
+of,O
+New,O
+Guineans,O
+and,O
+Bougainville,O
+Islanders,O
+have,O
+inherited,O
+a,O
+proportion,O
+of,O
+their,O
+ancestry,O
+from,O
+Denisovans,O
+,,O
+an,O
+archaic,O
+hominin,O
+group,O
+from,O
+Siberia,O
+.,O
+ , 
+However,O
+,,O
+only,O
+a,O
+sparse,O
+sampling,O
+of,O
+populations,O
+from,O
+Southeast,O
+Asia,O
+and,O
+Oceania,O
+were,O
+analyzed,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+quantify,O
+Denisova,O
+admixture,O
+in,O
+33,O
+additional,O
+populations,O
+from,O
+Asia,O
+and,O
+Oceania,O
+.,O
+ , 
+Aboriginal,O
+Australians,O
+,,O
+Near,O
+Oceanians,O
+,,O
+Polynesians,O
+,,O
+Fijians,O
+,,O
+east,O
+Indonesians,O
+,,O
+and,O
+Mamanwa,O
+(,O
+a,O
+",O
+Negrito,O
+",O
+group,O
+from,O
+the,O
+Philippines,O
+),O
+have,O
+all,O
+inherited,O
+genetic,O
+material,O
+from,O
+Denisovans,O
+,,O
+but,O
+mainland,O
+East,O
+Asians,O
+,,O
+western,O
+Indonesians,O
+,,O
+Jehai,O
+(,O
+a,O
+Negrito,O
+group,O
+from,O
+Malaysia,O
+),O
+,,O
+and,O
+Onge,O
+(,O
+a,O
+Negrito,O
+group,O
+from,O
+the,O
+Andaman,O
+Islands,O
+),O
+have,O
+not,O
+.,O
+ , 
+These,O
+results,O
+indicate,O
+that,O
+Denisova,O
+gene,O
+flow,O
+occurred,O
+into,O
+the,O
+common,O
+ancestors,O
+of,O
+New,O
+Guineans,O
+,,O
+Australians,O
+,,O
+and,O
+Mamanwa,O
+but,O
+not,O
+into,O
+the,O
+ancestors,O
+of,O
+the,O
+Jehai,O
+and,O
+Onge,O
+and,O
+suggest,O
+that,O
+relatives,O
+of,O
+present,O
+-,O
+day,O
+East,O
+Asians,O
+were,O
+not,O
+in,O
+Southeast,O
+Asia,O
+when,O
+the,O
+Denisova,O
+gene,O
+flow,O
+occurred,O
+.,O
+ , 
+Our,O
+finding,O
+that,O
+descendants,O
+of,O
+the,O
+earliest,O
+inhabitants,O
+of,O
+Southeast,O
+Asia,O
+do,O
+not,O
+all,O
+harbor,O
+Denisova,O
+admixture,O
+is,O
+inconsistent,O
+with,O
+a,O
+history,O
+in,O
+which,O
+the,O
+Denisova,O
+interbreeding,O
+occurred,O
+in,O
+mainland,O
+Asia,O
+and,O
+then,O
+spread,O
+over,O
+Southeast,O
+Asia,O
+,,O
+leading,O
+to,O
+all,O
+its,O
+earliest,O
+modern,O
+human,O
+inhabitants,O
+.,O
+ , 
+Instead,O
+,,O
+the,O
+data,O
+can,O
+be,O
+most,O
+parsimoniously,O
+explained,O
+if,O
+the,O
+Denisova,O
+gene,O
+flow,O
+occurred,O
+in,O
+Southeast,O
+Asia,O
+itself,O
+.,O
+ , 
+Thus,O
+,,O
+archaic,O
+Denisovans,O
+must,O
+have,O
+lived,O
+over,O
+an,O
+extraordinarily,O
+broad,O
+geographic,O
+and,O
+ecological,O
+range,O
+,,O
+from,O
+Siberia,O
+to,O
+tropical,O
+Asia,O
+.,O
+ , 
+#1284474
+Mutation,O
+creating,O
+a,O
+new,O
+splice,O
+site,O
+in,O
+the,O
+growth,O
+hormone,O
+receptor,O
+genes,O
+of,O
+37,O
+Ecuadorean,O
+patients,O
+with,O
+Laron,O
+syndrome,O
+.,O
+ , 
+Laron,O
+syndrome,O
+is,O
+an,O
+autosomal,O
+recessive,O
+condition,O
+characterized,O
+by,O
+resistance,O
+to,O
+growth,O
+hormone,O
+.,O
+ , 
+We,O
+sought,O
+to,O
+determine,O
+the,O
+molecular,O
+basis,O
+of,O
+this,O
+condition,O
+in,O
+an,O
+Ecuadorean,O
+population,O
+with,O
+a,O
+high,O
+incidence,O
+of,O
+affected,O
+individuals,O
+.,O
+ , 
+Growth,O
+hormone,O
+receptor,O
+gene,O
+sequences,O
+from,O
+an,O
+obligate,O
+heterozygote,O
+were,O
+amplified,O
+by,O
+the,O
+polymerase,O
+chain,O
+reaction,O
+and,O
+screened,O
+for,O
+mutations,O
+using,O
+denaturing,O
+gradient,O
+gel,O
+electrophoresis,O
+.,O
+ , 
+Only,O
+exon,O
+6,O
+revealed,O
+homo-,O
+and,O
+heteroduplexes,O
+on,O
+denaturing,O
+gradient,O
+gels,O
+.,O
+ , 
+Sequencing,O
+revealed,O
+a,O
+substitution,O
+of,O
+guanine,O
+for,O
+adenine,O
+in,O
+the,O
+third,O
+position,O
+of,O
+codon,O
+180,O
+that,O
+did,O
+not,O
+change,O
+the,O
+amino,O
+acid,O
+encoded,O
+.,O
+ , 
+Sequencing,O
+of,O
+the,O
+exon,O
+6,O
+-,O
+exon,O
+7,O
+splice,O
+junction,O
+from,O
+RNA,O
+-,O
+polymerase,O
+chain,O
+reaction,O
+amplified,O
+cellular,O
+RNA,O
+of,O
+an,O
+affected,O
+individual,O
+revealed,O
+that,O
+the,O
+substitution,O
+activates,O
+a,O
+5,O
+',O
+splice,O
+site,O
+24,O
+nucleotides,O
+upstream,O
+from,O
+the,O
+normal,O
+exon,O
+6,O
+-,O
+intron,O
+6,O
+boundary,O
+.,O
+ , 
+Splicing,O
+in,O
+two,O
+probands,O
+',O
+lymphoblasts,O
+occurred,O
+virtually,O
+exclusively,O
+at,O
+the,O
+abnormal,O
+5,O
+',O
+splice,O
+site,O
+created,O
+by,O
+the,O
+codon,O
+180,O
+substitution,O
+.,O
+ , 
+Exon,O
+6,O
+sequences,O
+from,O
+38,O
+patients,O
+and,O
+47,O
+relatives,O
+were,O
+amplified,O
+and,O
+analyzed,O
+by,O
+sequencing,O
+or,O
+dot,O
+-,O
+blot,O
+hybridization,O
+with,O
+allele,O
+-,O
+specific,O
+oligonucleotides,O
+.,O
+ , 
+The,O
+substitution,O
+was,O
+detected,O
+in,O
+74,O
+of,O
+76,O
+Laron,O
+syndrome,O
+patients,O
+',O
+GH,O
+-,O
+receptor,O
+alleles,O
+.,O
+ , 
+All,O
+26,O
+parents,O
+and,O
+12,O
+of,O
+21,O
+unaffected,O
+siblings,O
+were,O
+heterozygous,O
+for,O
+this,O
+mutation,O
+.,O
+ , 
+It,O
+was,O
+absent,O
+in,O
+61,O
+unrelated,O
+unaffected,O
+control,O
+individuals,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+the,O
+codon,O
+180,O
+nucleotide,O
+substitution,O
+probably,O
+causes,O
+Laron,O
+syndrome,O
+as,O
+translation,O
+of,O
+the,O
+observed,O
+,,O
+abnormally,O
+spliced,O
+growth,O
+hormone,O
+receptor,O
+transcript,O
+would,O
+lead,O
+to,O
+the,O
+synthesis,O
+of,O
+a,O
+receptor,O
+protein,O
+with,O
+an,O
+8,O
+amino,O
+acid,O
+deletion,O
+from,O
+the,O
+extracellular,O
+domain,O
+.,O
+ , 
+#19576565
+Deficiency,O
+of,O
+Dol,O
+-,O
+P,O
+-,O
+Man,O
+synthase,O
+subunit,O
+DPM3,B-Gene
+bridges,O
+the,O
+congenital,O
+disorders,O
+of,O
+glycosylation,O
+with,O
+the,O
+dystroglycanopathies,O
+.,O
+ , 
+Alpha,O
+-,O
+dystroglycanopathies,O
+such,O
+as,O
+Walker,O
+Warburg,O
+syndrome,O
+represent,O
+an,O
+important,O
+subgroup,O
+of,O
+the,O
+muscular,O
+dystrophies,O
+that,O
+have,O
+been,O
+related,O
+to,O
+defective,O
+O,O
+-,O
+mannosylation,O
+of,O
+alpha,O
+-,O
+dystroglycan,O
+.,O
+ , 
+In,O
+many,O
+patients,O
+,,O
+the,O
+underlying,O
+genetic,O
+etiology,O
+remains,O
+unsolved,O
+.,O
+ , 
+Isolated,O
+muscular,O
+dystrophy,O
+has,O
+not,O
+been,O
+described,O
+in,O
+the,O
+congenital,O
+disorders,O
+of,O
+glycosylation,O
+(,O
+CDG,O
+),O
+caused,O
+by,O
+N,O
+-,O
+linked,O
+protein,O
+glycosylation,O
+defects,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+present,O
+a,O
+genetic,O
+N,O
+-,O
+glycosylation,O
+disorder,O
+with,O
+muscular,O
+dystrophy,O
+in,O
+the,O
+group,O
+of,O
+CDG,O
+type,O
+I.,O
+Extensive,O
+biochemical,O
+investigations,O
+revealed,O
+a,O
+strongly,O
+reduced,O
+dolichol,O
+-,O
+phosphate,O
+-,O
+mannose,O
+(,O
+Dol,O
+-,O
+P,O
+-,O
+Man,O
+),O
+synthase,O
+activity,O
+.,O
+ , 
+Sequencing,O
+of,O
+the,O
+three,O
+DPM,O
+subunits,O
+and,O
+complementation,O
+of,O
+DPM3,O
+-,O
+deficient,O
+CHO2.38,O
+cells,O
+showed,O
+a,O
+pathogenic,O
+p.,B-SNP
+L85S,I-SNP
+missense,O
+mutation,O
+in,O
+the,O
+strongly,O
+conserved,O
+coiled,O
+-,O
+coil,O
+domain,O
+of,O
+DPM3,B-Gene
+that,O
+tethers,O
+catalytic,O
+DPM1,B-Gene
+to,O
+the,O
+ER,O
+membrane,O
+.,O
+ , 
+Cotransfection,O
+experiments,O
+in,O
+CHO,O
+cells,O
+showed,O
+a,O
+reduced,O
+binding,O
+capacity,O
+of,O
+DPM3(L85S,B-Gene
+),I-SNP
+for,O
+DPM1,B-Gene
+.,I-Gene
+ , 
+Investigation,O
+of,O
+the,O
+four,O
+Dol,O
+-,O
+P,O
+-,O
+Man,O
+-,O
+dependent,O
+glycosylation,O
+pathways,O
+in,O
+the,O
+ER,O
+revealed,O
+strongly,O
+reduced,O
+O,O
+-,O
+mannosylation,O
+of,O
+alpha,O
+-,O
+dystroglycan,O
+in,O
+a,O
+muscle,O
+biopsy,O
+,,O
+thereby,O
+explaining,O
+the,O
+clinical,O
+phenotype,O
+of,O
+muscular,O
+dystrophy,O
+.,O
+ , 
+This,O
+mild,O
+Dol,O
+-,O
+P,O
+-,O
+Man,O
+biosynthesis,O
+defect,O
+due,O
+to,O
+DPM3,B-Gene
+mutations,O
+is,O
+a,O
+cause,O
+for,O
+alpha,O
+-,O
+dystroglycanopathy,O
+,,O
+thereby,O
+bridging,O
+the,O
+congenital,O
+disorders,O
+of,O
+glycosylation,O
+with,O
+the,O
+dystroglycanopathies,O
+.,O
+ , 
+#18423522
+Estimating,O
+odds,O
+ratios,O
+in,O
+genome,O
+scans,O
+:,O
+an,O
+approximate,O
+conditional,O
+likelihood,O
+approach,O
+.,O
+ , 
+In,O
+modern,O
+whole,O
+-,O
+genome,O
+scans,O
+,,O
+the,O
+use,O
+of,O
+stringent,O
+thresholds,O
+to,O
+control,O
+the,O
+genome,O
+-,O
+wide,O
+testing,O
+error,O
+distorts,O
+the,O
+estimation,O
+process,O
+,,O
+producing,O
+estimated,O
+effect,O
+sizes,O
+that,O
+may,O
+be,O
+on,O
+average,O
+far,O
+greater,O
+in,O
+magnitude,O
+than,O
+the,O
+true,O
+effect,O
+sizes,O
+.,O
+ , 
+We,O
+introduce,O
+a,O
+method,O
+,,O
+based,O
+on,O
+the,O
+estimate,O
+of,O
+genetic,O
+effect,O
+and,O
+its,O
+standard,O
+error,O
+as,O
+reported,O
+by,O
+standard,O
+statistical,O
+software,O
+,,O
+to,O
+correct,O
+for,O
+this,O
+bias,O
+in,O
+case,O
+-,O
+control,O
+association,O
+studies,O
+.,O
+ , 
+Our,O
+approach,O
+is,O
+widely,O
+applicable,O
+,,O
+is,O
+far,O
+easier,O
+to,O
+implement,O
+than,O
+competing,O
+approaches,O
+,,O
+and,O
+may,O
+often,O
+be,O
+applied,O
+to,O
+published,O
+studies,O
+without,O
+access,O
+to,O
+the,O
+original,O
+data,O
+.,O
+ , 
+We,O
+evaluate,O
+the,O
+performance,O
+of,O
+our,O
+approach,O
+via,O
+extensive,O
+simulations,O
+for,O
+a,O
+range,O
+of,O
+genetic,O
+models,O
+,,O
+minor,O
+allele,O
+frequencies,O
+,,O
+and,O
+genetic,O
+effect,O
+sizes,O
+.,O
+ , 
+Compared,O
+to,O
+the,O
+naive,O
+estimation,O
+procedure,O
+,,O
+our,O
+approach,O
+reduces,O
+the,O
+bias,O
+and,O
+the,O
+mean,O
+squared,O
+error,O
+,,O
+especially,O
+for,O
+modest,O
+effect,O
+sizes,O
+.,O
+ , 
+We,O
+also,O
+develop,O
+a,O
+principled,O
+method,O
+to,O
+construct,O
+confidence,O
+intervals,O
+for,O
+the,O
+genetic,O
+effect,O
+that,O
+acknowledges,O
+the,O
+conditioning,O
+on,O
+statistical,O
+significance,O
+.,O
+ , 
+Our,O
+approach,O
+is,O
+described,O
+in,O
+the,O
+specific,O
+context,O
+of,O
+odds,O
+ratios,O
+and,O
+logistic,O
+modeling,O
+but,O
+is,O
+more,O
+widely,O
+applicable,O
+.,O
+ , 
+Application,O
+to,O
+recently,O
+published,O
+data,O
+sets,O
+demonstrates,O
+the,O
+relevance,O
+of,O
+our,O
+approach,O
+to,O
+modern,O
+genome,O
+scans,O
+.,O
+ , 
+#18394579
+A,O
+mutation,O
+in,O
+HOXA2,B-Gene
+is,O
+responsible,O
+for,O
+autosomal,O
+-,O
+recessive,O
+microtia,O
+in,O
+an,O
+Iranian,O
+family,O
+.,O
+ , 
+Microtia,O
+,,O
+a,O
+congenital,O
+deformity,O
+manifesting,O
+as,O
+an,O
+abnormally,O
+shaped,O
+or,O
+absent,O
+external,O
+ear,O
+,,O
+occurs,O
+in,O
+one,O
+out,O
+of,O
+8,000,O
+-,O
+10,000,O
+births,O
+.,O
+ , 
+We,O
+ascertained,O
+a,O
+consanguineous,O
+Iranian,O
+family,O
+segregating,O
+with,O
+autosomal,O
+-,O
+recessive,O
+bilateral,O
+microtia,O
+,,O
+mixed,O
+symmetrical,O
+severe,O
+to,O
+profound,O
+hearing,O
+impairment,O
+,,O
+and,O
+partial,O
+cleft,O
+palate,O
+.,O
+ , 
+Genome,O
+-,O
+wide,O
+linkage,O
+analysis,O
+localized,O
+the,O
+responsible,O
+gene,O
+to,O
+chromosome,O
+7p14.3,O
+-,O
+p15.3,O
+with,O
+a,O
+maximum,O
+multi,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+4.17,O
+.,O
+ , 
+In,O
+this,O
+region,O
+,,O
+homeobox,O
+genes,O
+from,O
+the,O
+HOXA,O
+cluster,O
+were,O
+the,O
+most,O
+interesting,O
+candidates,O
+.,O
+ , 
+Subsequent,O
+DNA,O
+sequence,O
+analysis,O
+of,O
+the,O
+HOXA1,B-Gene
+and,O
+HOXA2,B-Gene
+homeobox,O
+genes,O
+from,O
+the,O
+candidate,O
+region,O
+identified,O
+an,O
+interesting,O
+HOXA2,B-Gene
+homeodomain,O
+variant,O
+:,O
+a,O
+change,O
+in,O
+a,O
+highly,O
+conserved,O
+amino,O
+acid,O
+(,B-SNP
+p.,I-SNP
+Q186,I-SNP
+K,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+variant,O
+was,O
+not,O
+found,O
+in,O
+231,O
+Iranian,O
+and,O
+109,O
+Belgian,O
+control,O
+samples,O
+.,O
+ , 
+The,O
+critical,O
+contribution,O
+of,O
+HoxA2,B-Gene
+for,O
+auditory,O
+-,O
+system,O
+development,O
+has,O
+already,O
+been,O
+shown,O
+in,O
+mouse,O
+models,O
+.,O
+ , 
+We,O
+built,O
+a,O
+homology,O
+model,O
+to,O
+predict,O
+the,O
+effect,O
+of,O
+this,O
+mutation,O
+on,O
+the,O
+structure,O
+and,O
+DNA,O
+-,O
+binding,O
+activity,O
+of,O
+the,O
+homeodomain,O
+by,O
+using,O
+the,O
+program,O
+Modeler,O
+8v2,O
+.,O
+ , 
+In,O
+the,O
+model,O
+of,O
+the,O
+mutant,O
+homeodomain,O
+,,O
+the,O
+position,O
+of,O
+the,O
+mutant,O
+lysine,O
+side,O
+chain,O
+is,O
+consistently,O
+farther,O
+away,O
+from,O
+a,O
+nearby,O
+phosphate,O
+group,O
+;,O
+this,O
+altered,O
+position,O
+results,O
+in,O
+the,O
+loss,O
+of,O
+a,O
+hydrogen,O
+bond,O
+and,O
+affects,O
+the,O
+DNA,O
+-,O
+binding,O
+activity,O
+.,O
+ , 
+#7550228
+Detection,O
+and,O
+genetic,O
+analysis,O
+of,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+by,O
+competitive,O
+oligopriming,O
+.,O
+ , 
+A,O
+new,O
+approach,O
+for,O
+the,O
+detection,O
+of,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+has,O
+been,O
+applied,O
+,,O
+based,O
+on,O
+competitive,O
+oligonucleotide,O
+priming,O
+(,O
+COP,O
+),O
+of,O
+in,O
+vitro,O
+DNA,O
+amplification,O
+at,O
+the,O
+mutation,O
+site,O
+.,O
+ , 
+This,O
+method,O
+allows,O
+genotyping,O
+of,O
+the,O
+template,O
+DNA,O
+,,O
+through,O
+differential,O
+labeling,O
+of,O
+the,O
+allele,O
+-,O
+specific,O
+competitive,O
+oligoprimers,O
+and,O
+biotinylation,O
+of,O
+the,O
+common,O
+reverse,O
+primer,O
+.,O
+ , 
+The,O
+system,O
+provides,O
+a,O
+basis,O
+for,O
+rapid,O
+,,O
+simple,O
+,,O
+and,O
+reliable,O
+detection,O
+of,O
+the,O
+numerous,O
+known,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+,,O
+revealing,O
+the,O
+precise,O
+nature,O
+of,O
+the,O
+mismatch,O
+in,O
+each,O
+case,O
+,,O
+and,O
+thereby,O
+facilitating,O
+the,O
+molecular,O
+genetic,O
+analysis,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+#7981720
+Molecular,O
+characterization,O
+of,O
+a,O
+DDEI,O
+melting,O
+polymorphism,O
+at,O
+the,O
+angiotensin,B-Gene
+I,I-Gene
+-,I-Gene
+converting,I-Gene
+enzyme,I-Gene
+(,B-Gene
+ACE,I-Gene
+),I-Gene
+locus,O
+.,O
+ , 
+#10338100
+A,O
+single,O
+,,O
+large,O
+deletion,O
+accounts,O
+for,O
+all,O
+the,O
+beta,O
+-,O
+globin,O
+gene,O
+mutations,O
+in,O
+twenty,O
+families,O
+from,O
+Sabah,O
+(,O
+North,O
+Borneo,O
+),O
+,,O
+Malaysia,O
+.,O
+ , 
+Mutation,O
+in,O
+brief,O
+no,O
+.,O
+240,O
+.,O
+ , 
+Online,O
+.,O
+ , 
+Beta,O
+-,O
+thalassemia,O
+major,O
+is,O
+one,O
+of,O
+the,O
+commonest,O
+genetic,O
+disorders,O
+in,O
+South,O
+-,O
+East,O
+Asia,O
+.,O
+ , 
+The,O
+spectrum,O
+of,O
+beta,O
+-,O
+thalassemia,O
+mutations,O
+in,O
+the,O
+various,O
+ethnic,O
+sub,O
+-,O
+populations,O
+on,O
+the,O
+island,O
+of,O
+Borneo,O
+is,O
+unknown,O
+.,O
+ , 
+We,O
+studied,O
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+It,O
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+#17924341
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+When,O
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+Otherwise,O
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+Our,O
+results,O
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+a,O
+basis,O
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+the,O
+design,O
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+interpretation,O
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+point,O
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+importance,O
+of,O
+a,O
+clear,O
+distinction,O
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+#20021999
+Loss,O
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+.,O
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+We,O
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+a,O
+large,O
+Chinese,O
+family,O
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+X,O
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+critical,O
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+a,O
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+5.41,O
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+Mutation,O
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+gene,O
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+three,O
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+DFN2,O
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+PRPS1,B-Gene
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+These,O
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+PRPP,O
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+1,O
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+,,O
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+in,O
+silico,O
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+analysis,O
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+in,O
+vitro,O
+by,O
+enzymatic,O
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+assays,O
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+and,O
+fibroblasts,O
+from,O
+patients,O
+.,O
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+By,O
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+hybridization,O
+,,O
+we,O
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+expression,O
+of,O
+Prps1,B-Gene
+in,O
+murine,O
+vestibular,O
+and,O
+cochlea,O
+hair,O
+cells,O
+,,O
+with,O
+continuous,O
+expression,O
+in,O
+hair,O
+cells,O
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+expression,O
+in,O
+the,O
+spiral,O
+ganglion,O
+.,O
+ , 
+Being,O
+the,O
+second,O
+identified,O
+gene,O
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+with,O
+X,O
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+deafness,O
+,,O
+PRPS1,B-Gene
+will,O
+be,O
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+good,O
+candidate,O
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+genetic,O
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+X,O
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+hearing,O
+loss,O
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+ , 
+#14610717
+Allelic,O
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+ , 
+De,O
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+element-1,O
+,,O
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+L1,O
+),O
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+responsible,O
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+.,O
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+Previously,O
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+a,O
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+factor,O
+VIII,O
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+in,O
+a,O
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+hemophilia,O
+A.,O
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+subsequently,O
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+shown,O
+to,O
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+human,O
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+Here,O
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+in,O
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+human,O
+HeLa,O
+cells,O
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+Chimera,O
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+two,O
+amino,O
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+(,B-SNP
+S1259L,I-SNP
+and,O
+I1220,B-SNP
+M,I-SNP
+),I-SNP
+downstream,O
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+conserved,O
+cysteine,O
+-,O
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+in,O
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+open,O
+reading,O
+frame,O
+2,O
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+responsible,O
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+.,O
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+Thus,O
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+L1,O
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+potential,O
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+ , 
+We,O
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+such,O
+allelic,O
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+influence,O
+the,O
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+load,O
+present,O
+in,O
+an,O
+individual,O
+genome,O
+.,O
+ , 
+#20466092
+The,O
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+HapMap,O
+project,O
+:,O
+some,O
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+chi,O
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+ , 
+#19012875
+Divergence,O
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+from,O
+a,O
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+Although,O
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+,,O
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+less,O
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+We,O
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+relationship,O
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+LD,O
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+.,O
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+We,O
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+HapMap,O
+Phase,O
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+Summed,O
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+LD,O
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+African,O
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+up,O
+to,O
+approximately,O
+0.3,O
+cM.,O
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+We,O
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+Theory,O
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+#10090915
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+#15359380
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+Studies,O
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+In,O
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+lymphoblastoid,O
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+We,O
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+,,O
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+normal,O
+individuals,O
+,,O
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+radiation,O
+exposure,O
+.,O
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+By,O
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+that,O
+there,O
+is,O
+evidence,O
+of,O
+a,O
+heritable,O
+component,O
+to,O
+this,O
+variation,O
+.,O
+ , 
+The,O
+postradiation,O
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+expression,O
+level,O
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+genes,O
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+ferredoxin,B-Gene
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+FDXR,I-Gene
+),I-Gene
+and,O
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+cyclin,B-Gene
+-,I-Gene
+dependent,I-Gene
+kinase,I-Gene
+inhibitor,I-Gene
+1A,I-Gene
+gene,O
+(,B-Gene
+CDKN1A,I-Gene
+),I-Gene
+,,O
+is,O
+significantly,O
+greater,O
+(,O
+P<.001,O
+),O
+among,O
+twin,O
+pairs,O
+than,O
+within,O
+twin,O
+pairs,O
+.,O
+ , 
+The,O
+induction,O
+of,O
+FDXR,B-Gene
+by,O
+radiation,O
+showed,O
+a,O
+bimodal,O
+distribution,O
+.,O
+ , 
+Our,O
+findings,O
+have,O
+important,O
+implications,O
+for,O
+understanding,O
+the,O
+genetic,O
+basis,O
+of,O
+radiation,O
+response,O
+,,O
+which,O
+has,O
+remained,O
+largely,O
+unknown,O
+due,O
+to,O
+the,O
+lack,O
+of,O
+family,O
+material,O
+needed,O
+for,O
+genetic,O
+studies,O
+.,O
+ , 
+Our,O
+approach,O
+,,O
+which,O
+uses,O
+expression,O
+phenotypes,O
+in,O
+cell,O
+lines,O
+,,O
+allows,O
+us,O
+to,O
+expose,O
+cells,O
+from,O
+family,O
+members,O
+to,O
+radiation,O
+.,O
+ , 
+Similar,O
+study,O
+design,O
+can,O
+be,O
+applied,O
+to,O
+dissect,O
+the,O
+genetic,O
+basis,O
+of,O
+other,O
+complex,O
+human,O
+traits,O
+.,O
+ , 
+#16826523
+Submicroscopic,O
+deletion,O
+in,O
+patients,O
+with,O
+Williams,O
+-,O
+Beuren,O
+syndrome,O
+influences,O
+expression,O
+levels,O
+of,O
+the,O
+nonhemizygous,O
+flanking,O
+genes,O
+.,O
+ , 
+Genomic,O
+imbalance,O
+is,O
+a,O
+common,O
+cause,O
+of,O
+phenotypic,O
+abnormalities,O
+.,O
+ , 
+We,O
+measured,O
+the,O
+relative,O
+expression,O
+level,O
+of,O
+genes,O
+that,O
+map,O
+within,O
+the,O
+microdeletion,O
+that,O
+causes,O
+Williams,O
+-,O
+Beuren,O
+syndrome,O
+and,O
+within,O
+its,O
+flanking,O
+regions,O
+.,O
+ , 
+We,O
+found,O
+,,O
+unexpectedly,O
+,,O
+that,O
+not,O
+only,O
+hemizygous,O
+genes,O
+but,O
+also,O
+normal,O
+-,O
+copy,O
+neighboring,O
+genes,O
+show,O
+decreased,O
+relative,O
+levels,O
+of,O
+expression,O
+.,O
+ , 
+Our,O
+results,O
+suggest,O
+that,O
+not,O
+only,O
+the,O
+aneuploid,O
+genes,O
+but,O
+also,O
+the,O
+flanking,O
+genes,O
+that,O
+map,O
+several,O
+megabases,O
+away,O
+from,O
+a,O
+genomic,O
+rearrangement,O
+should,O
+be,O
+considered,O
+possible,O
+contributors,O
+to,O
+the,O
+phenotypic,O
+variation,O
+in,O
+genomic,O
+disorders,O
+.,O
+ , 
+#15449241
+Family,O
+-,O
+based,O
+association,O
+study,O
+of,O
+synapsin,B-Gene
+II,I-Gene
+and,O
+schizophrenia,O
+.,O
+ , 
+Synapsin,B-Gene
+II,I-Gene
+has,O
+been,O
+proposed,O
+as,O
+a,O
+candidate,O
+gene,O
+for,O
+vulnerability,O
+to,O
+schizophrenia,O
+on,O
+the,O
+basis,O
+of,O
+its,O
+function,O
+and,O
+its,O
+location,O
+in,O
+a,O
+region,O
+of,O
+the,O
+genome,O
+implicated,O
+by,O
+linkage,O
+studies,O
+in,O
+families,O
+with,O
+schizophrenia,O
+.,O
+ , 
+We,O
+recently,O
+reported,O
+positive,O
+association,O
+of,O
+synapsin,B-Gene
+II,I-Gene
+with,O
+schizophrenia,O
+in,O
+a,O
+case,O
+-,O
+control,O
+study,O
+(,O
+Chen,O
+et,O
+al,O
+.,O
+2004,O
+),O
+.,O
+ , 
+However,O
+,,O
+since,O
+case,O
+-,O
+control,O
+analyses,O
+can,O
+generate,O
+false,O
+-,O
+positive,O
+results,O
+in,O
+the,O
+presence,O
+of,O
+minor,O
+degrees,O
+of,O
+population,O
+stratification,O
+,,O
+we,O
+have,O
+performed,O
+a,O
+replication,O
+study,O
+in,O
+366,O
+additional,O
+Han,O
+Chinese,O
+probands,O
+and,O
+their,O
+parents,O
+by,O
+use,O
+of,O
+analyses,O
+of,O
+transmission,O
+/,O
+disequilibrium,O
+for,O
+three,O
+in,O
+/,O
+del,O
+markers,O
+and,O
+three,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+.,O
+ , 
+Positive,O
+association,O
+was,O
+observed,O
+for,O
+rs2307981,O
+(,O
+P,O
+=,O
+.02,O
+),O
+,,O
+rs2308169,O
+(,O
+P,O
+=,O
+.005,O
+),O
+,,O
+rs308963,O
+(,O
+P,O
+=,O
+.002,O
+),O
+,,O
+rs795009,O
+(,O
+P,O
+=,O
+.02,O
+),O
+,,O
+and,O
+rs2307973,O
+(,O
+P,O
+=,O
+.02,O
+),O
+.,O
+ , 
+For,O
+transmission,O
+of,O
+six,O
+-,O
+marker,O
+haplotypes,O
+,,O
+the,O
+global,O
+P,O
+value,O
+was.0000016,O
+(,O
+5,O
+degrees,O
+of,O
+freedom,O
+),O
+,,O
+principally,O
+because,O
+of,O
+overtransmission,O
+of,O
+the,O
+most,O
+common,O
+haplotype,O
+,,O
+CAA/-/G,O
+/,O
+T,O
+/,O
+C/-,O
+(,O
+frequency,O
+53.6,O
+%,O
+;,O
+chi,O
+(,O
+2,O
+),O
+=,O
+20.8,O
+;,O
+P,O
+=,O
+.0000051,O
+),O
+.,O
+ , 
+This,O
+confirms,O
+our,O
+previous,O
+study,O
+and,O
+provides,O
+further,O
+support,O
+for,O
+the,O
+role,O
+of,O
+synapsin,B-Gene
+II,I-Gene
+variants,O
+in,O
+susceptibility,O
+to,O
+schizophrenia,O
+.,O
+ , 
+#14740322
+PBAT,O
+:,O
+tools,O
+for,O
+family,O
+-,O
+based,O
+association,O
+studies,O
+.,O
+ , 
+#9452089
+3,O
+',O
+Acceptor,O
+splice,O
+site,O
+mutation,O
+in,O
+intron,O
+50,O
+leads,O
+to,O
+mild,O
+Duchenne,O
+muscular,O
+dystrophy,O
+phenotype,O
+.,O
+ , 
+#18439549
+The,O
+dawn,O
+of,O
+human,O
+matrilineal,O
+diversity,O
+.,O
+ , 
+The,O
+quest,O
+to,O
+explain,O
+demographic,O
+history,O
+during,O
+the,O
+early,O
+part,O
+of,O
+human,O
+evolution,O
+has,O
+been,O
+limited,O
+because,O
+of,O
+the,O
+scarce,O
+paleoanthropological,O
+record,O
+from,O
+the,O
+Middle,O
+Stone,O
+Age,O
+.,O
+ , 
+To,O
+shed,O
+light,O
+on,O
+the,O
+structure,O
+of,O
+the,O
+mitochondrial,O
+DNA,O
+(,O
+mtDNA,O
+),O
+phylogeny,O
+at,O
+the,O
+dawn,O
+of,O
+Homo,O
+sapiens,O
+,,O
+we,O
+constructed,O
+a,O
+matrilineal,O
+tree,O
+composed,O
+of,O
+624,O
+complete,O
+mtDNA,O
+genomes,O
+from,O
+sub,O
+-,O
+Saharan,O
+Hg,O
+L,O
+lineages,O
+.,O
+ , 
+We,O
+paid,O
+particular,O
+attention,O
+to,O
+the,O
+Khoi,O
+and,O
+San,O
+(,O
+Khoisan,O
+),O
+people,O
+of,O
+South,O
+Africa,O
+because,O
+they,O
+are,O
+considered,O
+to,O
+be,O
+a,O
+unique,O
+relic,O
+of,O
+hunter,O
+-,O
+gatherer,O
+lifestyle,O
+and,O
+to,O
+carry,O
+paternal,O
+and,O
+maternal,O
+lineages,O
+belonging,O
+to,O
+the,O
+deepest,O
+clades,O
+known,O
+among,O
+modern,O
+humans,O
+.,O
+ , 
+Both,O
+the,O
+tree,O
+phylogeny,O
+and,O
+coalescence,O
+calculations,O
+suggest,O
+that,O
+Khoisan,O
+matrilineal,O
+ancestry,O
+diverged,O
+from,O
+the,O
+rest,O
+of,O
+the,O
+human,O
+mtDNA,O
+pool,O
+90,000,O
+-,O
+150,000,O
+years,O
+before,O
+present,O
+(,O
+ybp,O
+),O
+and,O
+that,O
+at,O
+least,O
+five,O
+additional,O
+,,O
+currently,O
+extant,O
+maternal,O
+lineages,O
+existed,O
+during,O
+this,O
+period,O
+in,O
+parallel,O
+.,O
+ , 
+Furthermore,O
+,,O
+we,O
+estimate,O
+that,O
+a,O
+minimum,O
+of,O
+40,O
+other,O
+evolutionarily,O
+successful,O
+lineages,O
+flourished,O
+in,O
+sub,O
+-,O
+Saharan,O
+Africa,O
+during,O
+the,O
+period,O
+of,O
+modern,O
+human,O
+dispersal,O
+out,O
+of,O
+Africa,O
+approximately,O
+60,000,O
+-,O
+70,000,O
+ybp,O
+.,O
+ , 
+Only,O
+much,O
+later,O
+,,O
+at,O
+the,O
+beginning,O
+of,O
+the,O
+Late,O
+Stone,O
+Age,O
+,,O
+about,O
+40,000,O
+ybp,O
+,,O
+did,O
+introgression,O
+of,O
+additional,O
+lineages,O
+occur,O
+into,O
+the,O
+Khoisan,O
+mtDNA,O
+pool,O
+.,O
+ , 
+This,O
+process,O
+was,O
+further,O
+accelerated,O
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+the,O
+recent,O
+Bantu,O
+expansions,O
+.,O
+ , 
+Our,O
+results,O
+suggest,O
+that,O
+the,O
+early,O
+settlement,O
+of,O
+humans,O
+in,O
+Africa,O
+was,O
+already,O
+matrilineally,O
+structured,O
+and,O
+involved,O
+small,O
+,,O
+separately,O
+evolving,O
+isolated,O
+populations,O
+.,O
+ , 
+#1317992
+Increased,O
+genetic,O
+instability,O
+of,O
+the,O
+common,O
+fragile,O
+site,O
+at,O
+3p14,O
+after,O
+integration,O
+of,O
+exogenous,O
+DNA,O
+.,O
+ , 
+We,O
+determined,O
+previously,O
+that,O
+the,O
+selectable,O
+marker,O
+pSV2neo,O
+is,O
+preferentially,O
+inserted,O
+into,O
+chromosomal,O
+fragile,O
+sites,O
+in,O
+human,O
+x,O
+hamster,O
+hybrid,O
+cells,O
+in,O
+the,O
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+of,O
+an,O
+agent,O
+(,O
+aphidicolin,O
+),O
+that,O
+induces,O
+fragile,O
+-,O
+site,O
+expression,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+cells,O
+transfected,O
+without,O
+fragile,O
+-,O
+site,O
+induction,O
+showed,O
+an,O
+essentially,O
+random,O
+integration,O
+pattern,O
+.,O
+ , 
+To,O
+determine,O
+whether,O
+the,O
+integration,O
+of,O
+marker,O
+DNA,O
+at,O
+fragile,O
+sites,O
+affects,O
+the,O
+frequency,O
+of,O
+fragile,O
+-,O
+site,O
+expression,O
+,,O
+the,O
+parental,O
+hybrid,O
+and,O
+three,O
+transfectants,O
+(,O
+two,O
+with,O
+pSV2neo,O
+integrated,O
+at,O
+the,O
+fragile,O
+site,O
+at,O
+3p14.2,O
+[,B-Gene
+FRA3B,I-Gene
+],I-Gene
+and,O
+specific,O
+hamster,O
+fragile,O
+sites,O
+[,O
+chromosome,O
+1,O
+,,O
+bands,O
+q26,O
+-,O
+31,O
+,,O
+or,O
+mar2,O
+,,O
+bands,O
+q11,O
+-,O
+13,O
+],O
+and,O
+one,O
+with,O
+pSV2neo,O
+integrated,O
+at,O
+sites,O
+that,O
+are,O
+not,O
+fragile,O
+sites,O
+),O
+were,O
+treated,O
+with,O
+aphidicolin,O
+.,O
+ , 
+After,O
+24,O
+h,O
+the,O
+two,O
+cell,O
+lines,O
+with,O
+plasmid,O
+integration,O
+at,O
+FRA3B,B-Gene
+showed,O
+structural,O
+rearrangements,O
+at,O
+that,O
+site,O
+;,O
+these,O
+rearrangements,O
+accounted,O
+for,O
+43%-67,O
+%,O
+of,O
+the,O
+total,O
+deletions,O
+and,O
+translocations,O
+observed,O
+.,O
+ , 
+Structural,O
+rearrangements,O
+were,O
+not,O
+observed,O
+in,O
+the,O
+parental,O
+cell,O
+line,O
+.,O
+ , 
+After,O
+5,O
+d,O
+aphidicolin,O
+treatment,O
+,,O
+the,O
+observed,O
+excess,O
+in,O
+frequency,O
+of,O
+structural,O
+rearrangements,O
+at,O
+FRA3B,B-Gene
+in,O
+the,O
+cell,O
+lines,O
+with,O
+pSV2neo,O
+integration,O
+at,O
+3p14,O
+over,O
+that,O
+in,O
+the,O
+two,O
+lines,O
+without,O
+FRA3B,B-Gene
+integration,O
+was,O
+less,O
+dramatic,O
+,,O
+but,O
+nonetheless,O
+significant,O
+.,O
+ , 
+Fluorescent,O
+in,O
+situ,O
+hybridization,O
+(,O
+FISH,O
+),O
+analysis,O
+of,O
+these,O
+cells,O
+,,O
+using,O
+a,O
+biotin,O
+-,O
+labeled,O
+pSV2neo,O
+probe,O
+,,O
+showed,O
+results,O
+consistent,O
+with,O
+the,O
+gross,O
+rearrangements,O
+detected,O
+cytogenetically,O
+in,O
+the,O
+lines,O
+with,O
+FRA3B,B-Gene
+integration,O
+;,O
+however,O
+,,O
+the,O
+pSV2neo,O
+sequences,O
+were,O
+frequently,O
+deleted,O
+concomitantly,O
+with,O
+translocations.(ABSTRACT,O
+TRUNCATED,O
+AT,O
+250,O
+WORDS,O
+),O
+ , 
+#10775530
+Intragenic,O
+inversion,O
+of,O
+mtDNA,O
+:,O
+a,O
+new,O
+type,O
+of,O
+pathogenic,O
+mutation,O
+in,O
+a,O
+patient,O
+with,O
+mitochondrial,O
+myopathy,O
+.,O
+ , 
+We,O
+report,O
+an,O
+unusual,O
+molecular,O
+defect,O
+in,O
+the,O
+mitochondrially,O
+encoded,O
+ND1,B-Gene
+subunit,O
+of,O
+NADH,O
+ubiquinone,O
+oxidoreductase,O
+(,O
+complex,O
+I,O
+),O
+in,O
+a,O
+patient,O
+with,O
+mitochondrial,O
+myopathy,O
+and,O
+isolated,O
+complex,O
+I,O
+deficiency,O
+.,O
+ , 
+The,O
+mutation,O
+is,O
+an,O
+inversion,O
+of,O
+seven,O
+nucleotides,O
+within,O
+the,O
+ND1,B-Gene
+gene,O
+,,O
+which,O
+maintains,O
+the,O
+reading,O
+frame,O
+.,O
+ , 
+The,O
+inversion,O
+,,O
+which,O
+alters,O
+three,O
+highly,O
+conserved,O
+amino,O
+acids,O
+in,O
+the,O
+polypeptide,O
+,,O
+was,O
+heteroplasmic,O
+in,O
+the,O
+patient,O
+'s,O
+muscle,O
+but,O
+was,O
+not,O
+detectable,O
+in,O
+blood,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+a,O
+pathogenic,O
+inversion,O
+mutation,O
+in,O
+human,O
+mtDNA,O
+.,O
+ , 
+#10677321
+A,O
+coalescent,O
+approach,O
+to,O
+study,O
+linkage,O
+disequilibrium,O
+between,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+.,O
+ , 
+We,O
+present,O
+the,O
+results,O
+of,O
+extensive,O
+simulations,O
+that,O
+emulate,O
+the,O
+development,O
+and,O
+distribution,O
+of,O
+linkage,O
+disequilibrium,O
+(,O
+LD,O
+),O
+between,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+and,O
+a,O
+gene,O
+locus,O
+that,O
+is,O
+phenotypically,O
+stratified,O
+into,O
+two,O
+classes,O
+(,O
+disease,O
+phenotype,O
+and,O
+wild,O
+-,O
+type,O
+phenotype,O
+),O
+.,O
+ , 
+Our,O
+approach,O
+,,O
+based,O
+on,O
+coalescence,O
+theory,O
+,,O
+allows,O
+an,O
+explicit,O
+modeling,O
+of,O
+the,O
+demographic,O
+history,O
+of,O
+the,O
+population,O
+without,O
+conditioning,O
+on,O
+the,O
+age,O
+of,O
+the,O
+mutation,O
+,,O
+and,O
+serves,O
+as,O
+an,O
+efficient,O
+tool,O
+to,O
+carry,O
+out,O
+simulations,O
+.,O
+ , 
+More,O
+specifically,O
+,,O
+we,O
+compare,O
+the,O
+influence,O
+that,O
+a,O
+constant,O
+population,O
+size,O
+or,O
+an,O
+exponentially,O
+growing,O
+population,O
+has,O
+on,O
+the,O
+amount,O
+of,O
+LD,O
+.,O
+ , 
+These,O
+results,O
+indicate,O
+that,O
+attempts,O
+to,O
+locate,O
+single,O
+disease,O
+genes,O
+are,O
+most,O
+likely,O
+successful,O
+in,O
+small,O
+and,O
+constant,O
+populations,O
+.,O
+ , 
+On,O
+the,O
+other,O
+hand,O
+,,O
+if,O
+we,O
+consider,O
+an,O
+exponentially,O
+growing,O
+population,O
+that,O
+started,O
+to,O
+expand,O
+from,O
+an,O
+initially,O
+constant,O
+population,O
+of,O
+reasonable,O
+size,O
+,,O
+then,O
+our,O
+simulations,O
+indicate,O
+a,O
+lower,O
+success,O
+rate,O
+.,O
+ , 
+The,O
+power,O
+to,O
+detect,O
+association,O
+is,O
+enhanced,O
+if,O
+haplotypes,O
+constructed,O
+from,O
+several,O
+SNPs,O
+are,O
+used,O
+as,O
+markers,O
+.,O
+ , 
+The,O
+versatility,O
+of,O
+the,O
+coalescence,O
+approach,O
+also,O
+allows,O
+the,O
+analysis,O
+of,O
+other,O
+relevant,O
+factors,O
+that,O
+influence,O
+the,O
+chances,O
+that,O
+a,O
+disease,O
+gene,O
+will,O
+be,O
+located,O
+.,O
+ , 
+We,O
+show,O
+that,O
+several,O
+alleles,O
+leading,O
+to,O
+the,O
+same,O
+disease,O
+have,O
+no,O
+substantial,O
+influence,O
+on,O
+the,O
+amount,O
+of,O
+LD,O
+,,O
+as,O
+long,O
+as,O
+the,O
+differences,O
+between,O
+the,O
+disease,O
+-,O
+causing,O
+alleles,O
+are,O
+confined,O
+to,O
+the,O
+same,O
+region,O
+of,O
+the,O
+gene,O
+locus,O
+and,O
+as,O
+long,O
+as,O
+each,O
+allele,O
+occurs,O
+in,O
+an,O
+appreciable,O
+frequency,O
+.,O
+ , 
+Our,O
+simulations,O
+indicate,O
+that,O
+mapping,O
+of,O
+less,O
+-,O
+frequent,O
+diseases,O
+is,O
+more,O
+likely,O
+to,O
+be,O
+successful,O
+.,O
+ , 
+Moreover,O
+,,O
+we,O
+show,O
+that,O
+successful,O
+attempts,O
+to,O
+map,O
+complex,O
+diseases,O
+depend,O
+crucially,O
+on,O
+the,O
+phenotype,O
+-,O
+genotype,O
+correlations,O
+of,O
+all,O
+alleles,O
+at,O
+the,O
+disease,O
+locus,O
+.,O
+ , 
+An,O
+analysis,O
+of,O
+lipoprotein,O
+lipase,O
+data,O
+indicates,O
+that,O
+our,O
+simulations,O
+capture,O
+the,O
+major,O
+features,O
+of,O
+LD,O
+occurring,O
+in,O
+biological,O
+data,O
+.,O
+ , 
+#1609795
+The,O
+human,O
+gene,O
+encoding,O
+acetylcholinesterase,B-Gene
+is,O
+located,O
+on,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+7,O
+.,O
+ , 
+Acetylcholinesterase,B-Gene
+(,B-Gene
+AChE,I-Gene
+),I-Gene
+is,O
+a,O
+secreted,O
+enzyme,O
+essential,O
+for,O
+regulating,O
+cholinergic,O
+neurotransmission,O
+at,O
+neuronal,O
+and,O
+neuromuscular,O
+synapses,O
+.,O
+ , 
+In,O
+view,O
+of,O
+the,O
+altered,O
+expression,O
+of,O
+AChE,B-Gene
+in,O
+some,O
+central,O
+neurological,O
+and,O
+neuromuscular,O
+disorders,O
+with,O
+a,O
+probable,O
+genetic,O
+basis,O
+,,O
+we,O
+have,O
+identified,O
+the,O
+chromosomal,O
+location,O
+of,O
+the,O
+gene,O
+encoding,O
+AChE.,B-Gene
+ , 
+Chromosomal,O
+in,O
+situ,O
+suppression,O
+hybridization,O
+analysis,O
+revealed,O
+a,O
+single,O
+gene,O
+to,O
+be,O
+at,O
+7q22,O
+,,O
+a,O
+result,O
+which,O
+was,O
+confirmed,O
+by,O
+PCR,O
+analysis,O
+of,O
+genomic,O
+DNA,O
+from,O
+a,O
+human,O
+/,O
+hamster,O
+somatic,O
+cell,O
+hybrid,O
+containing,O
+a,O
+single,O
+human,O
+chromosome,O
+7,O
+.,O
+ , 
+The,O
+AChE,B-Gene
+gene,O
+thus,O
+maps,O
+to,O
+the,O
+same,O
+region,O
+in,O
+which,O
+frequent,O
+nonrandom,O
+chromosome,O
+7,O
+deletions,O
+occur,O
+in,O
+leukemias,O
+of,O
+myeloid,O
+cell,O
+precursors,O
+known,O
+to,O
+express,O
+the,O
+enzyme,O
+during,O
+normal,O
+differentiation,O
+.,O
+ , 
+#11283796
+Disruption,O
+of,O
+the,O
+bipartite,O
+imprinting,O
+center,O
+in,O
+a,O
+family,O
+with,O
+Angelman,O
+syndrome,O
+.,O
+ , 
+Imprinting,O
+in,O
+15q11,O
+-,O
+q13,O
+is,O
+controlled,O
+by,O
+a,O
+bipartite,O
+imprinting,O
+center,O
+(,O
+IC,O
+),O
+,,O
+which,O
+maps,O
+to,O
+the,O
+SNURF,B-Gene
+-,I-Gene
+SNRPN,I-Gene
+locus,O
+.,O
+ , 
+Deletions,O
+of,O
+the,O
+exon,O
+1,O
+region,O
+impair,O
+the,O
+establishment,O
+or,O
+maintenance,O
+of,O
+the,O
+paternal,O
+imprint,O
+and,O
+can,O
+cause,O
+Prader,O
+-,O
+Willi,O
+syndrome,O
+(,O
+PWS,O
+),O
+.,O
+ , 
+Deletions,O
+of,O
+a,O
+region,O
+35,O
+kb,O
+upstream,O
+of,O
+exon,O
+1,O
+impair,O
+maternal,O
+imprinting,O
+and,O
+can,O
+cause,O
+Angelman,O
+syndrome,O
+(,O
+AS,O
+),O
+.,O
+ , 
+So,O
+far,O
+,,O
+in,O
+all,O
+affected,O
+sibs,O
+with,O
+an,O
+imprinting,O
+defect,O
+,,O
+an,O
+inherited,O
+IC,O
+deletion,O
+was,O
+identified,O
+.,O
+ , 
+We,O
+report,O
+on,O
+two,O
+sibs,O
+with,O
+AS,O
+who,O
+do,O
+not,O
+have,O
+an,O
+IC,O
+deletion,O
+but,O
+instead,O
+have,O
+a,O
+1,O
+-,O
+1.5,O
+Mb,O
+inversion,O
+separating,O
+the,O
+two,O
+IC,O
+elements,O
+.,O
+ , 
+The,O
+inversion,O
+is,O
+transmitted,O
+silently,O
+through,O
+the,O
+male,O
+germline,O
+but,O
+impairs,O
+maternal,O
+imprinting,O
+after,O
+transmission,O
+through,O
+the,O
+female,O
+germline,O
+.,O
+ , 
+Our,O
+findings,O
+suggest,O
+that,O
+the,O
+close,O
+proximity,O
+and/or,O
+the,O
+correct,O
+orientation,O
+of,O
+the,O
+two,O
+IC,O
+elements,O
+are,O
+/,O
+is,O
+necessary,O
+for,O
+the,O
+establishment,O
+of,O
+a,O
+maternal,O
+imprint,O
+.,O
+ , 
+#14505274
+An,O
+Alu,O
+transposition,O
+model,O
+for,O
+the,O
+origin,O
+and,O
+expansion,O
+of,O
+human,O
+segmental,O
+duplications,O
+.,O
+ , 
+Relative,O
+to,O
+genomes,O
+of,O
+other,O
+sequenced,O
+organisms,O
+,,O
+the,O
+human,O
+genome,O
+appears,O
+particularly,O
+enriched,O
+for,O
+large,O
+,,O
+highly,O
+homologous,O
+segmental,O
+duplications,O
+(,O
+>,O
+or,O
+=,O
+90,O
+%,O
+sequence,O
+identity,O
+and,O
+>,O
+or,O
+=,O
+10,O
+kbp,O
+in,O
+length,O
+),O
+.,O
+ , 
+The,O
+molecular,O
+basis,O
+for,O
+this,O
+enrichment,O
+is,O
+unknown,O
+.,O
+ , 
+We,O
+sought,O
+to,O
+gain,O
+insight,O
+into,O
+the,O
+mechanism,O
+of,O
+origin,O
+,,O
+by,O
+systematically,O
+examining,O
+sequence,O
+features,O
+at,O
+the,O
+junctions,O
+of,O
+duplications,O
+.,O
+ , 
+We,O
+analyzed,O
+9,464,O
+junctions,O
+within,O
+regions,O
+of,O
+high,O
+-,O
+quality,O
+finished,O
+sequence,O
+from,O
+a,O
+genomewide,O
+set,O
+of,O
+2,366,O
+duplication,O
+alignments,O
+.,O
+ , 
+We,O
+observed,O
+a,O
+highly,O
+significant,O
+(,O
+P<.0001,O
+),O
+enrichment,O
+of,O
+Alu,O
+short,O
+interspersed,O
+element,O
+(,O
+SINE,O
+),O
+sequences,O
+near,O
+or,O
+within,O
+the,O
+junction,O
+.,O
+ , 
+Twenty,O
+-,O
+seven,O
+percent,O
+of,O
+all,O
+segmental,O
+duplications,O
+terminated,O
+within,O
+an,O
+Alu,O
+repeat,O
+.,O
+ , 
+The,O
+Alu,O
+junction,O
+enrichment,O
+was,O
+most,O
+pronounced,O
+for,O
+interspersed,O
+segmental,O
+duplications,O
+separated,O
+by,O
+>,O
+or,O
+=,O
+1,O
+Mb,O
+of,O
+intervening,O
+sequence,O
+.,O
+ , 
+Alu,O
+elements,O
+at,O
+the,O
+junctions,O
+showed,O
+higher,O
+levels,O
+of,O
+divergence,O
+,,O
+consistent,O
+with,O
+Alu,O
+-,O
+Alu,O
+-,O
+mediated,O
+recombination,O
+events,O
+.,O
+ , 
+When,O
+we,O
+classified,O
+Alu,O
+elements,O
+into,O
+major,O
+subfamilies,O
+,,O
+younger,O
+elements,O
+(,O
+AluY,O
+and,O
+AluS,O
+),O
+accounted,O
+for,O
+the,O
+enrichment,O
+,,O
+whereas,O
+the,O
+oldest,O
+primate,O
+family,O
+(,O
+AluJ,O
+),O
+showed,O
+no,O
+enrichment,O
+.,O
+ , 
+We,O
+propose,O
+that,O
+the,O
+primate,O
+-,O
+specific,O
+burst,O
+of,O
+Alu,O
+retroposition,O
+activity,O
+(,O
+which,O
+occurred,O
+35,O
+-,O
+40,O
+million,O
+years,O
+ago,O
+),O
+sensitized,O
+the,O
+ancestral,O
+human,O
+genome,O
+for,O
+Alu,O
+-,O
+Alu,O
+-,O
+mediated,O
+recombination,O
+events,O
+,,O
+which,O
+,,O
+in,O
+turn,O
+,,O
+initiated,O
+the,O
+expansion,O
+of,O
+gene,O
+-,O
+rich,O
+segmental,O
+duplications,O
+and,O
+their,O
+subsequent,O
+role,O
+in,O
+nonallelic,O
+homologous,O
+recombination,O
+.,O
+ , 
+#15338458
+Conventional,O
+multipoint,O
+nonparametric,O
+linkage,O
+analysis,O
+is,O
+not,O
+necessarily,O
+inherently,O
+biased,O
+.,O
+ , 
+#12900794
+A,O
+full,O
+-,O
+likelihood,O
+method,O
+for,O
+the,O
+evaluation,O
+of,O
+causality,O
+of,O
+sequence,O
+variants,O
+from,O
+family,O
+data,O
+.,O
+ , 
+In,O
+many,O
+disease,O
+genes,O
+,,O
+a,O
+substantial,O
+fraction,O
+of,O
+all,O
+rare,O
+variants,O
+detected,O
+can,O
+not,O
+yet,O
+be,O
+used,O
+for,O
+genetic,O
+counselling,O
+because,O
+of,O
+uncertainty,O
+about,O
+their,O
+association,O
+with,O
+disease,O
+.,O
+ , 
+One,O
+approach,O
+to,O
+the,O
+characterization,O
+of,O
+these,O
+unclassified,O
+variants,O
+is,O
+the,O
+analysis,O
+of,O
+patterns,O
+of,O
+cosegregation,O
+with,O
+disease,O
+in,O
+affected,O
+carrier,O
+families,O
+.,O
+ , 
+Petersen,O
+et,O
+al,O
+.,O
+ , 
+previously,O
+provided,O
+a,O
+simplistic,O
+Bayesian,O
+method,O
+for,O
+evaluation,O
+of,O
+causality,O
+of,O
+such,O
+sequence,O
+variants,O
+.,O
+ , 
+In,O
+the,O
+present,O
+report,O
+,,O
+we,O
+propose,O
+a,O
+more,O
+general,O
+method,O
+based,O
+on,O
+the,O
+full,O
+pedigree,O
+likelihood,O
+,,O
+and,O
+we,O
+show,O
+that,O
+the,O
+use,O
+of,O
+this,O
+method,O
+can,O
+provide,O
+more,O
+accurate,O
+and,O
+informative,O
+assessment,O
+of,O
+causality,O
+than,O
+could,O
+the,O
+previous,O
+method,O
+.,O
+ , 
+We,O
+further,O
+show,O
+that,O
+it,O
+is,O
+important,O
+that,O
+the,O
+pedigree,O
+information,O
+be,O
+as,O
+complete,O
+as,O
+possible,O
+and,O
+that,O
+the,O
+distinction,O
+be,O
+made,O
+between,O
+unaffected,O
+individuals,O
+and,O
+those,O
+of,O
+unknown,O
+phenotype,O
+.,O
+ , 
+#11438995
+Biosensor,O
+technology,O
+for,O
+real,O
+-,O
+time,O
+detection,O
+of,O
+the,O
+cystic,O
+fibrosis,O
+W1282X,B-SNP
+mutation,O
+in,O
+CFTR,B-Gene
+.,I-Gene
+ , 
+In,O
+the,O
+present,O
+paper,O
+,,O
+biospecific,O
+interaction,O
+analysis,O
+(,O
+BIA,O
+),O
+was,O
+performed,O
+using,O
+surface,O
+plasmon,O
+resonance,O
+(,O
+SPR,O
+),O
+and,O
+biosensor,O
+technologies,O
+to,O
+detect,O
+the,O
+Trp1282Ter,B-SNP
+mutation,O
+(,B-SNP
+W1282X,I-SNP
+),I-SNP
+of,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+(,I-Gene
+CF,I-Gene
+),I-Gene
+transmembrane,I-Gene
+conductance,I-Gene
+regulator,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+.,O
+ , 
+We,O
+first,O
+immobilized,O
+on,O
+a,O
+SA5,O
+sensor,O
+chip,O
+a,O
+single,O
+-,O
+stranded,O
+biotinylated,O
+oligonucleotide,O
+containing,O
+the,O
+sequence,O
+involved,O
+in,O
+this,O
+mutation,O
+,,O
+and,O
+the,O
+efficiency,O
+of,O
+hybridization,O
+of,O
+oligonucleotide,O
+probes,O
+differing,O
+in,O
+length,O
+was,O
+determined,O
+.,O
+ , 
+Second,O
+,,O
+we,O
+immobilized,O
+on,O
+different,O
+SA5,O
+sensor,O
+chips,O
+biotinylated,O
+polymerase,O
+-,O
+chain,O
+reaction,O
+(,O
+PCR,O
+),O
+products,O
+from,O
+a,O
+normal,O
+subject,O
+as,O
+well,O
+as,O
+from,O
+heterozygous,O
+and,O
+homozygous,O
+W1282X,B-SNP
+samples,O
+.,O
+ , 
+The,O
+results,O
+obtained,O
+show,O
+that,O
+both,O
+allele,O
+-,O
+specific,O
+10-,O
+and,O
+12,O
+-,O
+mer,O
+oligonucleotides,O
+are,O
+suitable,O
+probes,O
+to,O
+detect,O
+W1282X,B-SNP
+mutations,O
+of,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+gene,O
+under,O
+standard,O
+BIA,O
+experimental,O
+conditions,O
+.,O
+ , 
+During,O
+the,O
+association,O
+phase,O
+performed,O
+at,O
+25,O
+degrees,O
+C,O
+,,O
+discrimination,O
+between,O
+mismatched,O
+and,O
+full,O
+matched,O
+hybrids,O
+was,O
+readily,O
+and,O
+reproducibly,O
+observed,O
+by,O
+using,O
+the,O
+10,O
+-,O
+mer,O
+W1282X,B-SNP
+probes,O
+.,O
+ , 
+By,O
+contrast,O
+,,O
+when,O
+the,O
+12,O
+-,O
+mer,O
+DNA,O
+probes,O
+were,O
+employed,O
+,,O
+discrimination,O
+between,O
+mismatched,O
+and,O
+full,O
+matched,O
+hybrids,O
+was,O
+observed,O
+during,O
+the,O
+dissociation,O
+phase,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+the,O
+results,O
+presented,O
+suggest,O
+that,O
+BIA,O
+is,O
+an,O
+easy,O
+,,O
+speedy,O
+,,O
+and,O
+automatable,O
+approach,O
+to,O
+detect,O
+point,O
+mutations,O
+leading,O
+to,O
+cystic,O
+fibrosis,O
+.,O
+ , 
+By,O
+this,O
+procedure,O
+,,O
+it,O
+is,O
+possible,O
+to,O
+perform,O
+real,O
+-,O
+time,O
+monitoring,O
+of,O
+hybridization,O
+between,O
+target,O
+single,O
+stranded,O
+PCR,O
+products,O
+obtained,O
+by,O
+using,O
+as,O
+substrates,O
+DNA,O
+isolated,O
+from,O
+normal,O
+or,O
+heterozygous,O
+subjects,O
+,,O
+and,O
+homozygous,O
+W1282X,B-SNP
+CF,O
+samples,O
+and,O
+oligonucleotide,O
+probes,O
+,,O
+therefore,O
+enabling,O
+a,O
+one,O
+-,O
+step,O
+,,O
+non,O
+-,O
+radioactive,O
+protocol,O
+to,O
+perform,O
+diagnosis,O
+.,O
+ , 
+#17621637
+Lack,O
+of,O
+SSH1,B-Gene
+mutations,O
+in,O
+Dutch,O
+patients,O
+with,O
+disseminated,O
+superficial,O
+actinic,O
+porokeratosis,O
+:,O
+is,O
+there,O
+really,O
+an,O
+association,O
+?,O
+ , 
+#16960800
+A,O
+genomewide,O
+single,O
+-,O
+nucleotide,O
+-,O
+polymorphism,O
+panel,O
+with,O
+high,O
+ancestry,O
+information,O
+for,O
+African,O
+American,O
+admixture,O
+mapping,O
+.,O
+ , 
+Admixture,O
+mapping,O
+requires,O
+a,O
+genomewide,O
+panel,O
+of,O
+relatively,O
+evenly,O
+spaced,O
+markers,O
+that,O
+can,O
+distinguish,O
+the,O
+ancestral,O
+origins,O
+of,O
+chromosomal,O
+segments,O
+in,O
+admixed,O
+individuals,O
+.,O
+ , 
+Through,O
+use,O
+of,O
+the,O
+results,O
+of,O
+the,O
+International,O
+HapMap,O
+Project,O
+and,O
+specific,O
+selection,O
+criteria,O
+,,O
+the,O
+current,O
+study,O
+has,O
+examined,O
+the,O
+ability,O
+of,O
+selected,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+to,O
+extract,O
+continental,O
+ancestry,O
+information,O
+in,O
+African,O
+American,O
+subjects,O
+and,O
+to,O
+explore,O
+parameters,O
+for,O
+admixture,O
+mapping,O
+.,O
+ , 
+Genotyping,O
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+two,O
+linguistically,O
+diverse,O
+West,O
+African,O
+populations,O
+(,O
+Bini,O
+and,O
+Kanuri,O
+Nigerians,O
+,,O
+who,O
+are,O
+Niger,O
+-,O
+Congo,O
+[,O
+Bantu,O
+],O
+and,O
+Nilo,O
+-,O
+Saharan,O
+speakers,O
+,,O
+respectively,O
+),O
+,,O
+European,O
+Americans,O
+,,O
+and,O
+African,O
+Americans,O
+validated,O
+a,O
+genomewide,O
+set,O
+of,O
+>,O
+4,000,O
+SNP,O
+ancestry,O
+-,O
+informative,O
+markers,O
+with,O
+mean,O
+and,O
+median,O
+F(ST,O
+),O
+values,O
+>,O
+0.59,O
+and,O
+mean,O
+and,O
+median,O
+Fisher,O
+'s,O
+information,O
+content,O
+>,O
+2.5,O
+.,O
+ , 
+This,O
+set,O
+of,O
+SNPs,O
+extracted,O
+a,O
+larger,O
+amount,O
+of,O
+ancestry,O
+information,O
+in,O
+African,O
+Americans,O
+than,O
+previously,O
+reported,O
+SNP,O
+panels,O
+and,O
+provides,O
+nearly,O
+uniform,O
+coverage,O
+of,O
+the,O
+genome,O
+.,O
+ , 
+Moreover,O
+,,O
+in,O
+the,O
+current,O
+study,O
+,,O
+simulations,O
+show,O
+that,O
+this,O
+more,O
+informative,O
+panel,O
+improves,O
+power,O
+for,O
+admixture,O
+mapping,O
+in,O
+African,O
+Americans,O
+when,O
+ethnicity,O
+risk,O
+ratios,O
+are,O
+modest,O
+.,O
+ , 
+This,O
+is,O
+particularly,O
+important,O
+in,O
+the,O
+application,O
+of,O
+admixture,O
+mapping,O
+in,O
+complex,O
+genetic,O
+diseases,O
+for,O
+which,O
+only,O
+modest,O
+ethnicity,O
+risk,O
+ratios,O
+of,O
+relevant,O
+susceptibility,O
+genes,O
+are,O
+expected,O
+.,O
+ , 
+#8571955
+Modulation,O
+of,O
+the,O
+phenotype,O
+in,O
+dominant,O
+erythropoietic,O
+protoporphyria,O
+by,O
+a,O
+low,O
+expression,O
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+the,O
+normal,O
+ferrochelatase,O
+allele,O
+.,O
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+Erythropoietic,O
+protoporphyria,O
+(,O
+EPP,O
+),O
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+of,O
+the,O
+heme,O
+biosynthetic,O
+pathway,O
+due,O
+to,O
+ferrochelatase,O
+(,O
+FC,O
+),O
+deficiency,O
+.,O
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+EPP,O
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+generally,O
+considered,O
+to,O
+be,O
+transmitted,O
+as,O
+an,O
+autosomal,O
+dominant,O
+disease,O
+with,O
+incomplete,O
+penetrance,O
+,,O
+although,O
+autosomal,O
+recessive,O
+inheritance,O
+has,O
+been,O
+documented,O
+at,O
+the,O
+enzymatic,O
+and,O
+molecular,O
+level,O
+in,O
+some,O
+families,O
+.,O
+ , 
+In,O
+the,O
+dominant,O
+form,O
+of,O
+EPP,O
+,,O
+statistical,O
+analysis,O
+of,O
+FC,O
+activities,O
+documented,O
+a,O
+significantly,O
+lower,O
+mean,O
+value,O
+in,O
+patients,O
+than,O
+in,O
+asymptomatic,O
+carriers,O
+,,O
+suggesting,O
+a,O
+more,O
+complex,O
+mode,O
+of,O
+inheritance,O
+.,O
+ , 
+To,O
+account,O
+for,O
+these,O
+findings,O
+,,O
+we,O
+tested,O
+a,O
+multiallelic,O
+inheritance,O
+model,O
+in,O
+one,O
+EPP,O
+family,O
+in,O
+which,O
+the,O
+enzymatic,O
+data,O
+were,O
+compatible,O
+with,O
+this,O
+hypothesis,O
+.,O
+ , 
+In,O
+this,O
+EPP,O
+family,O
+,,O
+the,O
+specific,O
+FC,O
+gene,O
+mutation,O
+was,O
+an,O
+exon,O
+10,O
+skipping,O
+(,O
+delta,O
+Ex10,O
+),O
+,,O
+resulting,O
+from,O
+a,O
+G,O
+deletion,O
+within,O
+the,O
+exon,O
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+splice,O
+donor,O
+site,O
+.,O
+ , 
+The,O
+segregation,O
+of,O
+all,O
+FC,O
+alleles,O
+within,O
+the,O
+family,O
+was,O
+followed,O
+using,O
+the,O
+delta,O
+Ex10,O
+mutation,O
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+a,O
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+intragenic,O
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+(,B-SNP
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+/,I-SNP
+T,I-SNP
+),I-SNP
+.,O
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+mRNAs,O
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+from,O
+each,O
+FC,O
+allele,O
+were,O
+then,O
+subjected,O
+to,O
+relative,O
+quantification,O
+by,O
+a,O
+primer,O
+extension,O
+assay,O
+and,O
+to,O
+absolute,O
+quantification,O
+by,O
+a,O
+ribonuclease,O
+protection,O
+assay,O
+.,O
+ , 
+The,O
+data,O
+support,O
+the,O
+hypothesis,O
+that,O
+in,O
+this,O
+family,O
+the,O
+EPP,O
+phenotype,O
+results,O
+from,O
+the,O
+coinheritance,O
+of,O
+a,O
+low,O
+output,O
+normal,O
+FC,O
+allele,O
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+a,O
+mutant,O
+delta,O
+Ex10,O
+allele,O
+.,O
+ , 
+#12796855
+Selection,O
+of,O
+genetic,O
+markers,O
+for,O
+association,O
+analyses,O
+,,O
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+disequilibrium,O
+and,O
+haplotypes,O
+.,O
+ , 
+The,O
+genotyping,O
+of,O
+closely,O
+spaced,O
+single,O
+-,O
+nucleotide,O
+polymorphism,O
+(,O
+SNP,O
+),O
+markers,O
+frequently,O
+yields,O
+highly,O
+correlated,O
+data,O
+,,O
+owing,O
+to,O
+extensive,O
+linkage,O
+disequilibrium,O
+(,O
+LD,O
+),O
+between,O
+markers,O
+.,O
+ , 
+The,O
+extent,O
+of,O
+LD,O
+varies,O
+widely,O
+across,O
+the,O
+genome,O
+and,O
+drives,O
+the,O
+number,O
+of,O
+frequent,O
+haplotypes,O
+observed,O
+in,O
+small,O
+regions,O
+.,O
+ , 
+Several,O
+studies,O
+have,O
+illustrated,O
+the,O
+possibility,O
+that,O
+LD,O
+or,O
+haplotype,O
+data,O
+could,O
+be,O
+used,O
+to,O
+select,O
+a,O
+subset,O
+of,O
+SNPs,O
+that,O
+optimize,O
+the,O
+information,O
+retained,O
+in,O
+a,O
+genomic,O
+region,O
+while,O
+reducing,O
+the,O
+genotyping,O
+effort,O
+and,O
+simplifying,O
+the,O
+analysis,O
+.,O
+ , 
+We,O
+propose,O
+a,O
+method,O
+based,O
+on,O
+the,O
+spectral,O
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+the,O
+matrices,O
+of,O
+pairwise,O
+LD,O
+between,O
+markers,O
+,,O
+and,O
+we,O
+select,O
+markers,O
+on,O
+the,O
+basis,O
+of,O
+their,O
+contributions,O
+to,O
+the,O
+total,O
+genetic,O
+variation,O
+.,O
+ , 
+We,O
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+modify,O
+Clayton,O
+'s,O
+",O
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+tagging,O
+SNP,O
+",O
+selection,O
+method,O
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+which,O
+utilizes,O
+haplotype,O
+information,O
+.,O
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+For,O
+both,O
+methods,O
+,,O
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+propose,O
+sliding,O
+window,O
+-,O
+based,O
+algorithms,O
+that,O
+allow,O
+the,O
+methods,O
+to,O
+be,O
+applied,O
+to,O
+large,O
+chromosomal,O
+regions,O
+.,O
+ , 
+Our,O
+procedures,O
+require,O
+genotype,O
+information,O
+about,O
+a,O
+small,O
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+individuals,O
+for,O
+an,O
+initial,O
+set,O
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+selection,O
+of,O
+an,O
+optimum,O
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+of,O
+SNPs,O
+that,O
+could,O
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+efficiently,O
+genotyped,O
+on,O
+larger,O
+numbers,O
+of,O
+samples,O
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+retaining,O
+most,O
+of,O
+the,O
+genetic,O
+variation,O
+in,O
+samples,O
+.,O
+ , 
+We,O
+identify,O
+suitable,O
+parameter,O
+combinations,O
+for,O
+the,O
+procedures,O
+,,O
+and,O
+we,O
+show,O
+that,O
+a,O
+sample,O
+size,O
+of,O
+50,O
+-,O
+100,O
+individuals,O
+achieves,O
+consistent,O
+results,O
+in,O
+studies,O
+of,O
+simulated,O
+data,O
+sets,O
+in,O
+linkage,O
+equilibrium,O
+and,O
+LD,O
+.,O
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+When,O
+applied,O
+to,O
+experimental,O
+data,O
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+similarly,O
+effective,O
+at,O
+reducing,O
+the,O
+genotyping,O
+requirement,O
+while,O
+maintaining,O
+the,O
+genetic,O
+information,O
+content,O
+throughout,O
+the,O
+regions,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+haplotype,O
+-,O
+association,O
+results,O
+that,O
+Hosking,O
+et,O
+al,O
+.,O
+ , 
+obtained,O
+near,O
+CYP2D6,B-Gene
+were,O
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+identical,O
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+and,O
+after,O
+marker,O
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+ , 
+#10775524
+Identification,O
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+disomy,O
+following,O
+prenatal,O
+detection,O
+of,O
+Robertsonian,O
+translocations,O
+and,O
+isochromosomes,O
+.,O
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+Rearrangements,O
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+the,O
+acrocentric,O
+chromosomes,O
+(,O
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+translocations,O
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+isochromosomes,O
+),O
+are,O
+associated,O
+with,O
+an,O
+increased,O
+risk,O
+of,O
+aneuploidy,O
+.,O
+ , 
+Given,O
+this,O
+,,O
+and,O
+the,O
+large,O
+number,O
+of,O
+reported,O
+cases,O
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+uniparental,O
+disomy,O
+(,O
+UPD,O
+),O
+associated,O
+with,O
+an,O
+acrocentric,O
+rearrangement,O
+,,O
+carriers,O
+are,O
+presumed,O
+to,O
+be,O
+at,O
+risk,O
+for,O
+UPD,O
+.,O
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+However,O
+,,O
+an,O
+accurate,O
+risk,O
+estimate,O
+for,O
+UPD,O
+associated,O
+with,O
+these,O
+rearrangements,O
+is,O
+lacking,O
+.,O
+ , 
+A,O
+total,O
+of,O
+174,O
+prenatally,O
+identified,O
+acrocentric,O
+rearrangements,O
+,,O
+including,O
+both,O
+Robertsonian,O
+translocations,O
+and,O
+isochromosomes,O
+,,O
+were,O
+studied,O
+prospectively,O
+to,O
+identify,O
+UPD,O
+for,O
+the,O
+chromosomes,O
+involved,O
+in,O
+the,O
+rearrangements,O
+.,O
+ , 
+The,O
+overall,O
+goal,O
+of,O
+the,O
+study,O
+was,O
+to,O
+provide,O
+an,O
+estimate,O
+of,O
+the,O
+risk,O
+of,O
+UPD,O
+associated,O
+with,O
+nonhomologous,O
+Robertsonian,O
+translocations,O
+and,O
+homologous,O
+acrocentric,O
+rearrangements,O
+.,O
+ , 
+Of,O
+the,O
+168,O
+nonhomologous,O
+Robertsonian,O
+translocations,O
+studied,O
+,,O
+one,O
+showed,O
+UPD,O
+for,O
+chromosome,O
+13,O
+,,O
+providing,O
+a,O
+risk,O
+estimate,O
+of,O
+0.6,O
+%,O
+.,O
+ , 
+Four,O
+of,O
+the,O
+six,O
+homologous,O
+acrocentric,O
+rearrangements,O
+showed,O
+UPD,O
+,,O
+providing,O
+a,O
+risk,O
+estimate,O
+of,O
+66,O
+%,O
+.,O
+ , 
+These,O
+cases,O
+have,O
+also,O
+allowed,O
+delineation,O
+of,O
+the,O
+mechanisms,O
+involved,O
+in,O
+producing,O
+UPD,O
+unique,O
+to,O
+Robertsonian,O
+translocations,O
+.,O
+ , 
+Given,O
+the,O
+relatively,O
+high,O
+risk,O
+for,O
+UPD,O
+in,O
+prenatally,O
+identified,O
+Robertsonian,O
+translocations,O
+and,O
+isochromosomes,O
+,,O
+UPD,O
+testing,O
+should,O
+be,O
+considered,O
+,,O
+especially,O
+for,O
+cases,O
+involving,O
+the,O
+acrocentric,O
+chromosomes,O
+14,O
+and,O
+15,O
+,,O
+in,O
+which,O
+UPD,O
+is,O
+associated,O
+with,O
+adverse,O
+clinical,O
+outcomes,O
+.,O
+ , 
+#12552571
+Functional,O
+analysis,O
+of,O
+LKB1,B-Gene
+/,B-Gene
+STK11,I-Gene
+mutants,O
+and,O
+two,O
+aberrant,O
+isoforms,O
+found,O
+in,O
+Peutz,O
+-,O
+Jeghers,O
+Syndrome,O
+patients,O
+.,O
+ , 
+Peutz,O
+-,O
+Jeghers,O
+Syndrome,O
+(,O
+PJS,O
+),O
+is,O
+thought,O
+to,O
+be,O
+caused,O
+by,O
+mutations,O
+occurring,O
+in,O
+the,O
+widely,O
+expressed,O
+serine,O
+/,O
+threonine,O
+protein,O
+kinase,O
+named,O
+LKB1,B-Gene
+/,B-Gene
+STK11,I-Gene
+.,I-Gene
+ , 
+Recent,O
+work,O
+has,O
+led,O
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+of,O
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+mutants,O
+(,B-SNP
+R304W,I-SNP
+,,I-SNP
+I177N,B-SNP
+,,I-SNP
+K175,B-SNP
+-,I-SNP
+D176del,I-SNP
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+L263fsX286,B-SNP
+),I-SNP
+and,O
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+aberrant,O
+LKB1,B-Gene
+/,B-Gene
+STK11,I-Gene
+cDNA,O
+isoforms,O
+(,O
+r291,O
+-,O
+464del,O
+,,O
+r485,O
+-,O
+1283del,O
+),O
+in,O
+a,O
+group,O
+of,O
+PJS,O
+Italian,O
+patients,O
+.,O
+ , 
+Three,O
+of,O
+the,O
+four,O
+mutations,O
+only,O
+change,O
+1,O
+or,O
+2,O
+amino,O
+acids,O
+in,O
+the,O
+LKB1,B-Gene
+/,B-Gene
+STK11,I-Gene
+catalytic,O
+domain,O
+.,O
+ , 
+Here,O
+we,O
+demonstrate,O
+that,O
+all,O
+six,O
+LKB1,O
+/,O
+STK11,O
+variants,O
+analysed,O
+are,O
+completely,O
+inactive,O
+in,O
+vitro,O
+as,O
+they,O
+were,O
+unable,O
+to,O
+autophosphorylate,O
+at,O
+Thr336,O
+,,O
+the,O
+major,O
+LKB1,O
+/,O
+STK11,O
+autophosphorylation,O
+site,O
+,,O
+and,O
+to,O
+phosphorylate,O
+the,O
+p53,O
+tumour,O
+suppressor,O
+protein,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+5,O
+out,O
+of,O
+the,O
+6,O
+variants,O
+are,O
+entirely,O
+localised,O
+in,O
+the,O
+nucleus,O
+in,O
+contrast,O
+to,O
+the,O
+wild,O
+type,O
+LKB1,O
+/,O
+STK11,O
+,,O
+which,O
+is,O
+detected,O
+in,O
+both,O
+the,O
+nucleus,O
+and,O
+cytoplasm,O
+.,O
+ , 
+Finally,O
+we,O
+demonstrate,O
+that,O
+all,O
+6,O
+LKB1,O
+/,O
+STK11,O
+variants,O
+,,O
+in,O
+contrast,O
+to,O
+wild,O
+type,O
+LKB1,O
+/,O
+STK11,O
+,,O
+are,O
+unable,O
+to,O
+suppress,O
+the,O
+growth,O
+of,O
+melanoma,O
+G361,O
+cells,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+these,O
+results,O
+demonstrate,O
+that,O
+the,O
+LKB1,O
+mutations,O
+investigated,O
+in,O
+this,O
+study,O
+lead,O
+to,O
+the,O
+loss,O
+of,O
+serine,O
+/,O
+threonine,O
+kinase,O
+activity,O
+and,O
+are,O
+therefore,O
+likely,O
+to,O
+be,O
+the,O
+primary,O
+cause,O
+of,O
+PJS,O
+development,O
+in,O
+the,O
+patients,O
+that,O
+they,O
+were,O
+isolated,O
+from,O
+.,O
+ , 
+#9326322
+Analysis,O
+of,O
+the,O
+RPGR,B-Gene
+gene,O
+in,O
+11,O
+pedigrees,O
+with,O
+the,O
+retinitis,O
+pigmentosa,O
+type,O
+3,O
+genotype,O
+:,O
+paucity,O
+of,O
+mutations,O
+in,O
+the,O
+coding,O
+region,O
+but,O
+splice,O
+defects,O
+in,O
+two,O
+families,O
+.,O
+ , 
+X,O
+-,O
+linked,O
+retinitis,O
+pigmentosa,O
+(,O
+XLRP,O
+),O
+is,O
+a,O
+severe,O
+form,O
+of,O
+inherited,O
+progressive,O
+retinal,O
+degeneration,O
+.,O
+ , 
+The,O
+RP3,B-Gene
+(,O
+retinitis,O
+pigmentosa,O
+type,O
+3,O
+),O
+locus,O
+at,O
+Xp21.1,O
+is,O
+believed,O
+to,O
+account,O
+for,O
+the,O
+disease,O
+in,O
+the,O
+majority,O
+of,O
+XLRP,O
+families,O
+.,O
+ , 
+Linkage,O
+analysis,O
+and,O
+identification,O
+of,O
+patients,O
+with,O
+chromosomal,O
+deletion,O
+have,O
+refined,O
+the,O
+location,O
+of,O
+the,O
+RP3,B-Gene
+locus,O
+and,O
+recently,O
+have,O
+led,O
+to,O
+the,O
+cloning,O
+of,O
+the,O
+RPGR,B-Gene
+(,B-Gene
+retinitis,I-Gene
+pigmentosa,I-Gene
+GTPase,I-Gene
+regulator,I-Gene
+),I-Gene
+gene,O
+,,O
+which,O
+has,O
+been,O
+shown,O
+to,O
+be,O
+mutated,O
+in,O
+10%-15,O
+%,O
+of,O
+XLRP,O
+patients,O
+.,O
+ , 
+In,O
+order,O
+to,O
+systematically,O
+characterize,O
+the,O
+RPGR,B-Gene
+mutations,O
+,,O
+we,O
+identified,O
+11,O
+retinitis,O
+pigmentosa,O
+type,O
+III,O
+(,B-Gene
+RP3,I-Gene
+),I-Gene
+families,O
+by,O
+haplotype,O
+analysis,O
+.,O
+ , 
+Sequence,O
+analysis,O
+of,O
+the,O
+PCR,O
+-,O
+amplified,O
+genomic,O
+DNA,O
+from,O
+patients,O
+representing,O
+these,O
+RP3,B-Gene
+families,O
+did,O
+not,O
+reveal,O
+any,O
+causative,O
+mutation,O
+in,O
+RPGR,B-Gene
+exons,O
+2,O
+-,O
+19,O
+,,O
+spanning,O
+>,O
+98,O
+%,O
+of,O
+the,O
+coding,O
+region,O
+.,O
+ , 
+In,O
+patients,O
+from,O
+two,O
+families,O
+,,O
+we,O
+identified,O
+transition,O
+mutations,O
+in,O
+the,O
+intron,O
+region,O
+near,O
+splice,O
+sites,O
+(,O
+IVS10,O
++,O
+3,O
+and,O
+IVS13,O
+-,O
+8),O
+.,O
+ , 
+RNA,O
+analysis,O
+showed,O
+that,O
+both,O
+splice,O
+-,O
+site,O
+mutations,O
+resulted,O
+in,O
+the,O
+generation,O
+of,O
+aberrant,O
+RPGR,B-Gene
+transcripts,O
+.,O
+ , 
+Our,O
+results,O
+support,O
+the,O
+hypothesis,O
+that,O
+mutations,O
+in,O
+the,O
+reported,O
+RPGR,B-Gene
+gene,O
+are,O
+not,O
+a,O
+common,O
+defect,O
+in,O
+the,O
+RP3,B-Gene
+subtype,O
+of,O
+XLRP,O
+and,O
+that,O
+a,O
+majority,O
+of,O
+causative,O
+mutations,O
+may,O
+reside,O
+either,O
+in,O
+as,O
+yet,O
+unidentified,O
+RPGR,B-Gene
+exons,O
+or,O
+in,O
+another,O
+nearby,O
+gene,O
+at,O
+Xp21.1,O
+.,O
+ , 
+#17503322
+A,O
+genomewide,O
+admixture,O
+map,O
+for,O
+Latino,O
+populations,O
+.,O
+ , 
+Admixture,O
+mapping,O
+is,O
+an,O
+economical,O
+and,O
+powerful,O
+approach,O
+for,O
+localizing,O
+disease,O
+genes,O
+in,O
+populations,O
+of,O
+recently,O
+mixed,O
+ancestry,O
+and,O
+has,O
+proven,O
+successful,O
+in,O
+African,O
+Americans,O
+.,O
+ , 
+The,O
+method,O
+holds,O
+equal,O
+promise,O
+for,O
+Latinos,O
+,,O
+who,O
+typically,O
+inherit,O
+a,O
+mix,O
+of,O
+European,O
+,,O
+Native,O
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+,,O
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+African,O
+ancestry,O
+.,O
+ , 
+However,O
+,,O
+admixture,O
+mapping,O
+in,O
+Latinos,O
+has,O
+not,O
+been,O
+practical,O
+because,O
+of,O
+the,O
+lack,O
+of,O
+a,O
+map,O
+of,O
+ancestry,O
+-,O
+informative,O
+markers,O
+validated,O
+in,O
+Native,O
+American,O
+and,O
+other,O
+populations,O
+.,O
+ , 
+To,O
+address,O
+this,O
+,,O
+we,O
+screened,O
+multiple,O
+databases,O
+,,O
+containing,O
+millions,O
+of,O
+markers,O
+,,O
+to,O
+identify,O
+4,186,O
+markers,O
+that,O
+were,O
+putatively,O
+informative,O
+for,O
+determining,O
+the,O
+ancestry,O
+of,O
+chromosomal,O
+segments,O
+in,O
+Latino,O
+populations,O
+.,O
+ , 
+We,O
+experimentally,O
+validated,O
+each,O
+of,O
+these,O
+markers,O
+in,O
+at,O
+least,O
+232,O
+new,O
+Latino,O
+,,O
+European,O
+,,O
+Native,O
+American,O
+,,O
+and,O
+African,O
+samples,O
+,,O
+and,O
+we,O
+selected,O
+a,O
+subset,O
+of,O
+1,649,O
+markers,O
+to,O
+form,O
+an,O
+admixture,O
+map,O
+.,O
+ , 
+An,O
+advantage,O
+of,O
+our,O
+strategy,O
+is,O
+that,O
+we,O
+focused,O
+our,O
+map,O
+on,O
+markers,O
+distinguishing,O
+Native,O
+American,O
+from,O
+other,O
+ancestries,O
+and,O
+restricted,O
+it,O
+to,O
+markers,O
+with,O
+very,O
+similar,O
+frequencies,O
+in,O
+Europeans,O
+and,O
+Africans,O
+,,O
+which,O
+decreased,O
+the,O
+number,O
+of,O
+markers,O
+needed,O
+and,O
+minimized,O
+the,O
+possibility,O
+of,O
+false,O
+disease,O
+associations,O
+.,O
+ , 
+We,O
+evaluated,O
+the,O
+effectiveness,O
+of,O
+our,O
+map,O
+for,O
+localizing,O
+disease,O
+genes,O
+in,O
+four,O
+Latino,O
+populations,O
+from,O
+both,O
+North,O
+and,O
+South,O
+America,O
+.,O
+ , 
+#17041889
+Recessive,O
+arrhythmogenic,O
+right,O
+ventricular,O
+dysplasia,O
+due,O
+to,O
+novel,O
+cryptic,O
+splice,O
+mutation,O
+in,O
+PKP2,B-Gene
+.,I-Gene
+ , 
+Arrhythmogenic,O
+right,O
+ventricular,O
+dysplasia,O
+(,O
+ARVD,O
+),O
+is,O
+a,O
+genetic,O
+disorder,O
+resulting,O
+in,O
+fibro,O
+-,O
+fatty,O
+replacement,O
+of,O
+right,O
+ventricular,O
+myocytes,O
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+consequent,O
+ventricular,O
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+.,O
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+Heterozygous,O
+mutations,O
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+PKP2,B-Gene
+encoding,O
+plakophilin-2,B-Gene
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+previously,O
+been,O
+reported,O
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+reduced,O
+penetrance,O
+.,O
+ , 
+We,O
+report,O
+the,O
+first,O
+case,O
+of,O
+recessive,O
+ARVD,O
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+by,O
+mutations,O
+in,O
+PKP2,B-Gene
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+Candidate,O
+gene,O
+analysis,O
+in,O
+a,O
+typical,O
+proband,O
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+this,O
+disorder,O
+identified,O
+a,O
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+PKP2,B-Gene
+(,B-SNP
+c.[2484C,I-SNP
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+T]+[2484C,I-SNP
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+),O
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+to,O
+be,O
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+Gly828,I-SNP
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+Analysis,O
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+mRNA,O
+,,O
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+,,O
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+that,O
+this,O
+mutation,O
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+predominantly,O
+cryptic,O
+splicing,O
+,,O
+with,O
+a,O
+7,O
+-,O
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+in,O
+exon,O
+12,O
+.,O
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+The,O
+ensuing,O
+frame,O
+shift,O
+disrupts,O
+the,O
+last,O
+54,O
+amino,O
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+plakophilin-2,O
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+extends,O
+the,O
+open,O
+reading,O
+frame,O
+by,O
+145,O
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+3,O
+',O
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+.,O
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+Haplotype,O
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+of,O
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+Heterozygous,O
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+PKP2,B-Gene
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+manifestations,O
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+Further,O
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+#8116620
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+nonrandom,O
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+typing,O
+of,O
+16,O
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+alleles,O
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+a,O
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+480,O
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+bp,O
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+Two,O
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+same,O
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+Sequence,O
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+,,O
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+present,O
+in,O
+both,O
+alleles,O
+,,O
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+in,O
+the,O
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+these,O
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+in,O
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+28-,O
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+33,O
+-,O
+bp,O
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+a,O
+specific,O
+repeat,O
+pattern,O
+at,O
+the,O
+5,O
+',O
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+3,O
+',O
+ends,O
+of,O
+the,O
+region,O
+.,O
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+The,O
+genotype,O
+distribution,O
+for,O
+DXYS17,O
+in,O
+a,O
+Caucasian,O
+population,O
+did,O
+not,O
+deviate,O
+from,O
+the,O
+values,O
+expected,O
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+Hardy,O
+-,O
+Weinberg,O
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+.,O
+ , 
+However,O
+,,O
+the,O
+frequency,O
+of,O
+one,O
+allele,O
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+one,O
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+between,O
+males,O
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+females,O
+.,O
+ , 
+Segregation,O
+analysis,O
+showed,O
+that,O
+this,O
+difference,O
+was,O
+the,O
+result,O
+of,O
+a,O
+nonrandom,O
+distribution,O
+of,O
+certain,O
+alleles,O
+on,O
+the,O
+sex,O
+chromosomes,O
+in,O
+males,O
+.,O
+ , 
+#12402331
+Novel,O
+PEX1,B-Gene
+mutations,O
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+genotype,O
+-,O
+phenotype,O
+correlations,O
+in,O
+Australasian,O
+peroxisome,O
+biogenesis,O
+disorder,O
+patients,O
+.,O
+ , 
+The,O
+peroxisome,O
+biogenesis,O
+disorders,O
+(,O
+PBDs,O
+),O
+are,O
+a,O
+group,O
+of,O
+neuronal,O
+migration,O
+/,O
+neurodegenerative,O
+disorders,O
+that,O
+arise,O
+from,O
+defects,O
+in,O
+PEX,B-Gene
+genes,O
+.,O
+ , 
+A,O
+major,O
+subgroup,O
+of,O
+the,O
+PBDs,O
+includes,O
+Zellweger,O
+syndrome,O
+(,O
+ZS,O
+),O
+,,O
+neonatal,O
+adrenoleukodystrophy,O
+(,O
+NALD,O
+),O
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+infantile,O
+Refsum,O
+disease,O
+(,O
+IRD,O
+),O
+.,O
+ , 
+These,O
+three,O
+disorders,O
+represent,O
+a,O
+clinical,O
+continuum,O
+with,O
+Zellweger,O
+syndrome,O
+the,O
+most,O
+severe,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+PEX1,B-Gene
+gene,O
+,,O
+which,O
+encodes,O
+a,O
+protein,O
+of,O
+the,O
+AAA,O
+ATPase,O
+family,O
+involved,O
+in,O
+peroxisome,O
+matrix,O
+protein,O
+import,O
+,,O
+account,O
+for,O
+the,O
+genetic,O
+defect,O
+in,O
+more,O
+than,O
+half,O
+of,O
+the,O
+patients,O
+in,O
+this,O
+PBD,O
+subgroup,O
+.,O
+ , 
+We,O
+report,O
+here,O
+on,O
+the,O
+results,O
+of,O
+PEX1,B-Gene
+mutation,O
+detection,O
+in,O
+an,O
+Australasian,O
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+.,O
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+This,O
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+five,O
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+14,O
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+19,O
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+5,O
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+.,O
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+Significantly,O
+,,O
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+(,O
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+.,O
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+R798,I-SNP
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+PEX1,B-Gene
+function,O
+.,O
+ , 
+We,O
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+evaluated,O
+the,O
+cellular,O
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+of,O
+these,O
+novel,O
+mutations,O
+,,O
+along,O
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+PEX1,B-Gene
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+(,B-SNP
+c.2097,I-SNP
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+2098insT,I-SNP
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+),I-SNP
+,,O
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+mRNA,O
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+protein,O
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+The,O
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+consistent,O
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+a,O
+close,O
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+cellular,O
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+,,O
+disease,O
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+,,O
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+PEX1,O
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+#15739154
+Molecular,O
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+Pallister,O
+-,O
+Hall,O
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+type,O
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+GLI3,B-Gene
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+GLI3,B-Gene
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+that,O
+GLI3,B-Gene
+mutations,O
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+predict,O
+a,O
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+functional,O
+repressor,O
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+GLI3,B-Gene
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+.,O
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+To,O
+test,O
+these,O
+hypotheses,O
+,,O
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+patients,O
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+PHS,O
+and,O
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+GLI3,B-Gene
+mutations,O
+.,O
+ , 
+The,O
+patient,O
+group,O
+consisted,O
+of,O
+135,O
+individuals,O
+:,O
+89,O
+patients,O
+with,O
+GCPS,O
+and,O
+46,O
+patients,O
+with,O
+PHS,O
+.,O
+ , 
+We,O
+detected,O
+47,O
+pathological,O
+mutations,O
+(,O
+among,O
+60,O
+probands,O
+),O
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+.,O
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+First,O
+,,O
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+by,O
+many,O
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+alterations,O
+,,O
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+translocations,O
+,,O
+large,O
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+,,O
+exonic,O
+deletions,O
+and,O
+duplications,O
+,,O
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+,,O
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+/,O
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+,,O
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+splicing,O
+mutations,O
+.,O
+ , 
+In,O
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+,,O
+PHS,O
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+caused,O
+only,O
+by,O
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+/,O
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+splicing,O
+mutations,O
+.,O
+ , 
+Second,O
+,,O
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+the,O
+frameshift,O
+/,O
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+mutations,O
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+a,O
+clear,O
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+-,O
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+correlation,O
+.,O
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+Mutations,O
+in,O
+the,O
+first,O
+third,O
+of,O
+the,O
+gene,O
+(,O
+from,O
+open,O
+reading,O
+frame,O
+[,O
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+nucleotides,O
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+1,O
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+GCPS,O
+,,O
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+in,O
+the,O
+second,O
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+of,O
+the,O
+gene,O
+(,O
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+ORF,O
+nt,O
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+-,O
+3481,O
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+PHS,O
+.,O
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+Surprisingly,O
+,,O
+there,O
+were,O
+12,O
+mutations,O
+in,O
+patients,O
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+GCPS,O
+in,O
+the,O
+3,O
+',O
+third,O
+of,O
+the,O
+gene,O
+(,O
+after,O
+ORF,O
+nt,O
+3481,O
+),O
+,,O
+and,O
+no,O
+patients,O
+with,O
+PHS,O
+had,O
+mutations,O
+in,O
+this,O
+region,O
+.,O
+ , 
+These,O
+results,O
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+a,O
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+correlation,O
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+for,O
+GLI3,B-Gene
+mutations,O
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+pathogenesis,O
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+#7942859
+The,O
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+loci,O
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+The,O
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+(,O
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+#17701907
+Evidence,O
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+Here,O
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+Age,O
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+(,O
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+-,O
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+humans,O
+.,O
+ ,