Word,Tag
#23159251
An,O
exponential,O
combination,O
procedure,O
for,O
set,O
-,O
based,O
association,O
tests,O
in,O
sequencing,O
studies,O
.,O
 , 
State,O
-,O
of,O
-,O
the,O
-,O
art,O
next,O
-,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
that,O
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
be,O
associated,O
with,O
risk,O
or,O
phenotype,O
in,O
a,O
concerted,O
fashion,O
,,O
and,O
by,O
accumulating,O
information,O
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
literature,O
are,O
based,O
on,O
statistics,O
that,O
can,O
be,O
written,O
as,O
the,O
summation,O
of,O
variant,O
statistics,O
.,O
 , 
Here,O
,,O
we,O
propose,O
taking,O
the,O
summation,O
of,O
the,O
exponential,O
of,O
variant,O
statistics,O
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
of,O
the,O
exponential,O
of,O
variant,O
statistics,O
because,O
it,O
is,O
particularly,O
powerful,O
for,O
sparse,O
alternatives,O
-,O
that,O
is,O
,,O
compared,O
with,O
the,O
large,O
number,O
of,O
variants,O
being,O
tested,O
in,O
a,O
set,O
,,O
only,O
relatively,O
few,O
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
alleles,O
,,O
including,O
a,O
novel,O
mutation,O
,,O
characterize,O
beta,O
-,O
thalassemia,O
in,O
Ashkenazi,O
Jews,O
.,O
 , 
#9452104
Identification,O
of,O
four,O
novel,O
mutations,O
in,O
the,O
factor,B-Gene
VIII,I-Gene
gene,O
:,O
three,O
missense,O
mutations,O
(,B-SNP
E1875,I-SNP
G,I-SNP
,,I-SNP
G2088S,B-SNP
,,I-SNP
I2185,B-SNP
T,I-SNP
),I-SNP
and,O
a,O
2,O
-,O
bp,O
deletion,O
(,B-SNP
1780delTC,I-SNP
),I-SNP
.,O
 , 
#21665001
Hereditary,O
leukonychia,O
,,O
or,O
porcelain,O
nails,O
,,O
resulting,O
from,O
mutations,O
in,O
PLCD1,B-Gene
.,I-Gene
 , 
Hereditary,O
leukonychia,O
(,O
porcelain,O
nails,O
or,O
white,O
nails,O
),O
is,O
a,O
rare,O
nail,O
disorder,O
with,O
an,O
unknown,O
genetic,O
basis,O
.,O
 , 
To,O
identify,O
variants,O
in,O
a,O
gene,O
underlying,O
this,O
phenotype,O
,,O
we,O
identified,O
four,O
families,O
of,O
Pakistani,O
origin,O
showing,O
features,O
of,O
hereditary,O
leukonychia,O
.,O
 , 
All,O
20,O
nails,O
of,O
each,O
affected,O
individual,O
were,O
chalky,O
and,O
white,O
in,O
appearance,O
,,O
consistent,O
with,O
total,O
leukonychia,O
,,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
(,O
Z,O
),O
of,O
5.1,O
.,O
 , 
We,O
identified,O
pathogenic,O
mutations,O
in,O
PLCD1,B-Gene
in,O
all,O
four,O
families,O
,,O
which,O
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
a,O
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
was,O
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
and,O
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
reduced,O
enzymatic,O
activity,O
in,O
 ,O
vitro,O
.,O
 , 
Our,O
data,O
show,O
that,O
mutations,O
in,O
PLCD1,B-Gene
underlie,O
hereditary,O
leukonychia,O
,,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
mechanism,O
,,O
and,O
consequences,O
of,O
genetic,O
variation,O
,,O
for,O
recombination,O
rate,O
.,O
 , 
#20206336
Identification,O
of,O
a,O
recurrent,O
microdeletion,O
at,O
17q23.1q23.2,O
flanked,O
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
(,O
NAHR,O
),O
and,O
have,O
been,O
suggested,O
to,O
be,O
hot,O
spots,O
in,O
chromosome,O
evolution,O
and,O
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
by,O
microarray,O
-,O
based,O
comparative,O
genomic,O
hybridization,O
(,O
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
sequence,O
identity,O
and,O
in,O
the,O
same,O
orientation,O
.,O
 , 
One,O
of,O
the,O
deletions,O
is,O
approximately,O
2.8,O
Mb,O
in,O
size,O
and,O
is,O
flanked,O
on,O
the,O
distal,O
side,O
by,O
a,O
segmental,O
duplication,O
,,O
whereas,O
the,O
proximal,O
breakpoint,O
falls,O
between,O
segmental,O
duplications,O
.,O
 , 
These,O
characteristics,O
suggest,O
that,O
NAHR,O
mediated,O
six,O
out,O
of,O
seven,O
of,O
these,O
rearrangements,O
.,O
 , 
These,O
individuals,O
have,O
common,O
features,O
,,O
including,O
mild,O
to,O
moderate,O
developmental,O
delay,O
(,O
particularly,O
speech,O
delay,O
),O
,,O
microcephaly,O
,,O
postnatal,O
growth,O
retardation,O
,,O
heart,O
defects,O
,,O
and,O
hand,O
,,O
foot,O
,,O
and,O
limb,O
abnormalities,O
.,O
 , 
Although,O
all,O
individuals,O
had,O
at,O
least,O
mild,O
dysmorphic,O
facial,O
features,O
,,O
there,O
was,O
no,O
characteristic,O
constellation,O
of,O
features,O
that,O
would,O
elicit,O
clinical,O
suspicion,O
of,O
a,O
specific,O
disorder,O
.,O
 , 
The,O
identification,O
of,O
common,O
clinical,O
features,O
suggests,O
that,O
microdeletions,O
at,O
17q23.1q23.2,O
constitute,O
a,O
novel,O
syndrome,O
.,O
 , 
Furthermore,O
,,O
the,O
inclusion,O
in,O
the,O
minimal,O
deletion,O
region,O
of,O
TBX2,B-Gene
and,O
TBX4,B-Gene
,,I-Gene
transcription,O
factors,O
belonging,O
to,O
a,O
family,O
of,O
genes,O
implicated,O
in,O
a,O
variety,O
of,O
developmental,O
pathways,O
including,O
those,O
of,O
heart,O
and,O
limb,O
,,O
suggests,O
that,O
these,O
genes,O
may,O
play,O
an,O
important,O
role,O
in,O
the,O
phenotype,O
of,O
this,O
emerging,O
syndrome,O
.,O
 , 
#22365152
De,O
novo,O
pathogenic,O
SCN8A,B-Gene
mutation,O
identified,O
by,O
whole,O
-,O
genome,O
sequencing,O
of,O
a,O
family,O
quartet,O
affected,O
by,O
infantile,O
epileptic,O
encephalopathy,O
and,O
SUDEP,O
.,O
 , 
Individuals,O
with,O
severe,O
,,O
sporadic,O
disorders,O
of,O
infantile,O
onset,O
represent,O
an,O
important,O
class,O
of,O
disease,O
for,O
which,O
discovery,O
of,O
the,O
underlying,O
genetic,O
architecture,O
is,O
not,O
amenable,O
to,O
traditional,O
genetic,O
analysis,O
.,O
 , 
Full,O
-,O
genome,O
sequencing,O
of,O
affected,O
individuals,O
and,O
their,O
parents,O
provides,O
a,O
powerful,O
alternative,O
strategy,O
for,O
gene,O
discovery,O
.,O
 , 
We,O
performed,O
whole,O
-,O
genome,O
sequencing,O
(,O
WGS,O
),O
on,O
a,O
family,O
quartet,O
containing,O
an,O
affected,O
proband,O
and,O
her,O
unaffected,O
parents,O
and,O
sibling,O
.,O
 , 
The,O
15,O
-,O
year,O
-,O
old,O
female,O
proband,O
had,O
a,O
severe,O
epileptic,O
encephalopathy,O
consisting,O
of,O
early,O
-,O
onset,O
seizures,O
,,O
features,O
of,O
autism,O
,,O
intellectual,O
disability,O
,,O
ataxia,O
,,O
and,O
sudden,O
unexplained,O
death,O
in,O
epilepsy,O
.,O
 , 
We,O
discovered,O
a,O
de,O
novo,O
heterozygous,O
missense,O
mutation,O
(,B-SNP
c.5302A,I-SNP
>,I-SNP
G,I-SNP
 , 
[,B-SNP
p.,I-SNP
Asn1768Asp,I-SNP
],I-SNP
),O
in,O
the,O
voltage,O
-,O
gated,O
sodium,O
-,O
channel,O
gene,O
SCN8A,B-Gene
in,O
the,O
proband,O
.,O
 , 
This,O
mutation,O
alters,O
an,O
evolutionarily,O
conserved,O
residue,O
in,O
Nav1.6,O
,,O
one,O
of,O
the,O
most,O
abundant,O
sodium,O
channels,O
in,O
the,O
brain,O
.,O
 , 
Analysis,O
of,O
the,O
biophysical,O
properties,O
of,O
the,O
mutant,O
channel,O
demonstrated,O
a,O
dramatic,O
increase,O
in,O
persistent,O
sodium,O
current,O
,,O
incomplete,O
channel,O
inactivation,O
,,O
and,O
a,O
depolarizing,O
shift,O
in,O
the,O
voltage,O
dependence,O
of,O
steady,O
-,O
state,O
fast,O
inactivation,O
.,O
 , 
Current,O
-,O
clamp,O
analysis,O
in,O
hippocampal,O
neurons,O
transfected,O
with,O
p.,B-SNP
Asn1768Asp,I-SNP
channels,O
revealed,O
increased,O
spontaneous,O
firing,O
,,O
paroxysmal,O
-,O
depolarizing,O
-,O
shift,O
-,O
like,O
complexes,O
,,O
and,O
an,O
increased,O
firing,O
frequency,O
,,O
consistent,O
with,O
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
identifies,O
SCN8A,B-Gene
as,O
the,O
fifth,O
sodium,O
-,O
channel,O
gene,O
to,O
be,O
mutated,O
in,O
epilepsy,O
and,O
demonstrates,O
the,O
value,O
of,O
WGS,O
for,O
the,O
identification,O
of,O
pathogenic,O
mutations,O
causing,O
severe,O
,,O
sporadic,O
neurological,O
disorders,O
.,O
 , 
#12204007
Identification,O
of,O
mutations,O
of,O
Bruton,B-Gene
's,I-Gene
tyrosine,I-Gene
kinase,I-Gene
gene,O
(,B-Gene
BTK,I-Gene
),I-Gene
in,O
Brazilian,O
patients,O
with,O
X,O
-,O
linked,O
agammaglobulinemia,O
.,O
 , 
Mutations,O
in,O
the,O
Bruton,B-Gene
tyrosine,I-Gene
kinase,I-Gene
(,B-Gene
BTK,I-Gene
),I-Gene
gene,O
are,O
responsible,O
for,O
X,O
-,O
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
analysis,O
detected,O
mutations,O
in,O
10,O
of,O
the,O
13,O
presumed,O
XLA,O
families,O
.,O
 , 
Seven,O
mutations,O
(,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
of,O
the,O
BTK,B-Gene
gene,O
in,O
Brazilian,O
patients,O
.,O
 , 
#9915968
The,O
Glu318Gly,B-SNP
substitution,O
in,O
presenilin,B-Gene
1,I-Gene
is,O
not,O
causally,O
related,O
to,O
Alzheimer,O
disease,O
.,O
 , 
#22795537
De,O
novo,O
mutations,O
in,O
MLL,B-Gene
cause,O
Wiedemann,O
-,O
Steiner,O
syndrome,O
.,O
 , 
Excessive,O
growth,O
of,O
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
consistent,O
with,O
a,O
diagnosis,O
of,O
Wiedemann,O
-,O
Steiner,O
syndrome,O
(,O
WSS,O
),O
.,O
 , 
Utilizing,O
a,O
whole,O
-,O
exome,O
sequencing,O
approach,O
,,O
we,O
identified,O
de,O
novo,O
mutations,O
in,O
MLL,B-Gene
in,O
five,O
of,O
the,O
six,O
individuals,O
.,O
 , 
MLL,B-Gene
encodes,O
a,O
histone,O
methyltransferase,O
that,O
regulates,O
chromatin,O
-,O
mediated,O
transcription,O
through,O
the,O
catalysis,O
of,O
methylation,O
of,O
histone,O
H3K4,O
.,O
 , 
Each,O
of,O
the,O
five,O
mutations,O
is,O
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
arising,O
from,O
the,O
mutant,O
alleles,O
are,O
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
provide,O
additional,O
evidence,O
for,O
the,O
role,O
of,O
haploinsufficency,O
of,O
histone,O
-,O
modification,O
enzymes,O
in,O
multiple,O
-,O
congenital,O
-,O
anomaly,O
syndromes,O
,,O
and,O
further,O
illustrate,O
the,O
importance,O
of,O
the,O
regulation,O
of,O
histone,O
modification,O
in,O
development,O
.,O
 , 
#12740763
Identification,O
of,O
a,O
novel,O
gene,O
and,O
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
is,O
a,O
common,O
disease,O
with,O
an,O
established,O
genetic,O
component,O
that,O
presents,O
a,O
complex,O
mode,O
of,O
inheritance,O
.,O
 , 
While,O
studying,O
an,O
ancient,O
founder,O
population,O
in,O
Talana,O
,,O
a,O
village,O
in,O
Sardinia,O
,,O
we,O
recently,O
identified,O
a,O
susceptibility,O
locus,O
of,O
approximately,O
2.5,O
cM,O
for,O
UAN,O
on,O
10q21,O
-,O
q22,O
in,O
a,O
relatively,O
small,O
sample,O
that,O
was,O
carefully,O
selected,O
through,O
genealogical,O
information,O
.,O
 , 
To,O
refine,O
the,O
critical,O
region,O
and,O
to,O
identify,O
the,O
susceptibility,O
gene,O
,,O
we,O
extended,O
our,O
analysis,O
to,O
severely,O
affected,O
subjects,O
from,O
the,O
same,O
village,O
.,O
 , 
We,O
confirm,O
the,O
involvement,O
of,O
this,O
region,O
in,O
UAN,O
through,O
identical,O
-,O
by,O
-,O
descent,O
sharing,O
and,O
autozygosity,O
mapping,O
,,O
and,O
we,O
refine,O
the,O
critical,O
region,O
to,O
an,O
interval,O
of,O
approximately,O
67,O
kb,O
associated,O
with,O
UAN,O
by,O
linkage,O
-,O
disequilibrium,O
mapping,O
.,O
 , 
After,O
inspecting,O
the,O
genomic,O
sequences,O
available,O
in,O
public,O
databases,O
,,O
we,O
determined,O
that,O
a,O
novel,O
gene,O
overlaps,O
this,O
interval,O
.,O
 , 
This,O
gene,O
is,O
divided,O
into,O
15,O
exons,O
,,O
spanning,O
a,O
region,O
of,O
approximately,O
300,O
kb,O
and,O
generating,O
at,O
least,O
four,O
different,O
proteins,O
(,O
407,O
,,O
333,O
,,O
462,O
,,O
and,O
216,O
amino,O
acids,O
),O
.,O
 , 
Interestingly,O
,,O
the,O
last,O
isoform,O
was,O
completely,O
included,O
in,O
the,O
67,O
-,O
kb,O
associated,O
interval,O
.,O
 , 
Computer,O
-,O
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
at,O
N,O
-,O
termini,O
,,O
suggesting,O
that,O
it,O
could,O
be,O
an,O
integral,O
membrane,O
protein,O
.,O
 , 
Mutational,O
analysis,O
shows,O
that,O
a,O
coding,O
nucleotide,O
variant,O
(,B-SNP
Ala62Thr,I-SNP
),I-SNP
,,O
causing,O
a,O
missense,O
in,O
exon,O
12,O
,,O
is,O
in,O
strong,O
association,O
with,O
UAN,O
(,O
P=.0051,O
),O
.,O
 , 
Moreover,O
,,O
Ala62Thr,B-SNP
modifies,O
predicted,O
protein,O
secondary,O
structure,O
,,O
suggesting,O
that,O
it,O
may,O
have,O
a,O
role,O
in,O
UAN,O
etiology,O
.,O
 , 
The,O
present,O
study,O
underscores,O
the,O
value,O
of,O
our,O
small,O
,,O
genealogically,O
well,O
-,O
characterized,O
,,O
isolated,O
population,O
as,O
a,O
model,O
for,O
the,O
identification,O
of,O
susceptibility,O
genes,O
underlying,O
complex,O
diseases,O
.,O
 , 
Indeed,O
,,O
using,O
a,O
relatively,O
small,O
sample,O
of,O
affected,O
and,O
unaffected,O
subjects,O
,,O
we,O
identified,O
a,O
candidate,O
gene,O
for,O
multifactorial,O
UAN,O
.,O
 , 
#8352278
Statistical,O
evaluation,O
of,O
multiple,O
-,O
locus,O
linkage,O
data,O
in,O
experimental,O
species,O
and,O
its,O
relevance,O
to,O
human,O
studies,O
:,O
application,O
to,O
nonobese,O
diabetic,O
(,O
NOD,O
),O
mouse,O
and,O
human,O
insulin,O
-,O
dependent,O
diabetes,O
mellitus,O
(,O
IDDM,O
),O
.,O
 , 
Common,O
,,O
familial,O
human,O
disorders,O
generally,O
do,O
not,O
follow,O
Mendelian,O
inheritance,O
patterns,O
,,O
presumably,O
because,O
multiple,O
loci,O
are,O
involved,O
in,O
disease,O
susceptibility,O
.,O
 , 
One,O
approach,O
to,O
mapping,O
genes,O
for,O
such,O
traits,O
in,O
humans,O
is,O
to,O
first,O
study,O
an,O
analogous,O
form,O
in,O
an,O
animal,O
model,O
,,O
such,O
as,O
mouse,O
,,O
by,O
using,O
inbred,O
strains,O
and,O
backcross,O
experiments,O
.,O
 , 
Here,O
we,O
describe,O
methodology,O
for,O
analyzing,O
multiple,O
-,O
locus,O
linkage,O
data,O
from,O
such,O
experimental,O
backcrosses,O
,,O
particularly,O
in,O
light,O
of,O
multilocus,O
genetic,O
models,O
,,O
including,O
the,O
effects,O
of,O
epistasis,O
.,O
 , 
We,O
illustrate,O
these,O
methods,O
by,O
using,O
data,O
from,O
backcrosses,O
involving,O
nonobese,O
diabetic,O
mouse,O
,,O
which,O
serves,O
as,O
an,O
animal,O
model,O
for,O
human,O
insulin,O
-,O
dependent,O
diabetes,O
mellitus,O
.,O
 , 
We,O
show,O
that,O
it,O
is,O
likely,O
that,O
a,O
minimum,O
of,O
nine,O
loci,O
contribute,O
to,O
susceptibility,O
,,O
with,O
strong,O
epistasis,O
effects,O
among,O
these,O
loci,O
.,O
 , 
Three,O
of,O
the,O
loci,O
actually,O
confer,O
a,O
protective,O
effect,O
in,O
the,O
homozygote,O
,,O
compared,O
with,O
the,O
heterozygote,O
.,O
 , 
Further,O
,,O
we,O
discuss,O
the,O
relevance,O
of,O
these,O
studies,O
for,O
analogous,O
studies,O
of,O
the,O
human,O
form,O
of,O
the,O
trait,O
.,O
 , 
Specifically,O
,,O
we,O
show,O
that,O
the,O
magnitude,O
of,O
the,O
gene,O
effect,O
in,O
the,O
experimental,O
backcross,O
is,O
likely,O
to,O
correlate,O
only,O
weakly,O
,,O
at,O
best,O
,,O
with,O
the,O
expected,O
magnitude,O
of,O
effect,O
for,O
a,O
human,O
form,O
,,O
because,O
in,O
humans,O
the,O
gene,O
effect,O
will,O
depend,O
more,O
heavily,O
on,O
disease,O
allele,O
frequencies,O
than,O
on,O
the,O
observed,O
penetrance,O
ratios,O
;,O
such,O
allele,O
frequencies,O
are,O
unpredictable,O
.,O
 , 
Hence,O
,,O
the,O
major,O
benefit,O
from,O
animal,O
studies,O
may,O
be,O
a,O
better,O
understanding,O
of,O
the,O
disease,O
process,O
itself,O
,,O
rather,O
than,O
identification,O
of,O
cells,O
through,O
comparison,O
mapping,O
in,O
humans,O
by,O
using,O
regions,O
of,O
homology,O
.,O
 , 
#1609807
Anticipation,O
legitimized,O
:,O
unstable,O
DNA,O
to,O
the,O
rescue,O
.,O
 , 
#11951177
High,O
-,O
throughput,O
analysis,O
of,O
subtelomeric,O
chromosome,O
rearrangements,O
by,O
use,O
of,O
array,O
-,O
based,O
comparative,O
genomic,O
hybridization,O
.,O
 , 
Telomeric,O
chromosome,O
rearrangements,O
may,O
cause,O
mental,O
retardation,O
,,O
congenital,O
anomalies,O
,,O
and,O
miscarriages,O
.,O
 , 
Automated,O
detection,O
of,O
subtle,O
deletions,O
or,O
duplications,O
involving,O
telomeres,O
is,O
essential,O
for,O
high,O
-,O
throughput,O
diagnosis,O
,,O
but,O
impossible,O
when,O
conventional,O
cytogenetic,O
methods,O
are,O
used,O
.,O
 , 
Array,O
-,O
based,O
comparative,O
genomic,O
hybridization,O
(,O
CGH,O
),O
allows,O
high,O
-,O
resolution,O
screening,O
of,O
copy,O
number,O
abnormalities,O
by,O
hybridizing,O
differentially,O
labeled,O
test,O
and,O
reference,O
genomes,O
to,O
arrays,O
of,O
robotically,O
spotted,O
clones,O
.,O
 , 
To,O
assess,O
the,O
applicability,O
of,O
this,O
technique,O
in,O
the,O
diagnosis,O
of,O
(,O
sub)telomeric,O
imbalances,O
,,O
we,O
here,O
describe,O
a,O
blinded,O
study,O
,,O
in,O
which,O
DNA,O
from,O
20,O
patients,O
with,O
known,O
cytogenetic,O
abnormalities,O
involving,O
one,O
or,O
more,O
telomeres,O
was,O
hybridized,O
to,O
an,O
array,O
containing,O
a,O
validated,O
set,O
of,O
human,O
-,O
chromosome,O
-,O
specific,O
(,O
sub)telomere,O
probes,O
.,O
 , 
Single,O
-,O
copy,O
-,O
number,O
gains,O
and,O
losses,O
were,O
accurately,O
detected,O
on,O
these,O
arrays,O
,,O
and,O
an,O
excellent,O
concordance,O
between,O
the,O
original,O
cytogenetic,O
diagnosis,O
and,O
the,O
array,O
-,O
based,O
CGH,O
diagnosis,O
was,O
obtained,O
by,O
use,O
of,O
a,O
single,O
hybridization,O
.,O
 , 
In,O
addition,O
to,O
the,O
previously,O
identified,O
cytogenetic,O
changes,O
,,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
studied,O
.,O
 , 
The,O
robustness,O
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
of,O
a,O
novel,O
BBS,O
gene,O
(,B-Gene
BBS12,I-Gene
),I-Gene
highlights,O
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
the,O
tissue,B-Gene
-,I-Gene
nonspecific,I-Gene
alkaline,I-Gene
phosphatase,I-Gene
(,B-Gene
TNSALP,I-Gene
),I-Gene
gene,O
in,O
patients,O
with,O
severe,O
hypophosphatasia,O
.,O
 , 
Mutations,O
in,O
brief,O
no,O
.,O
217,O
.,O
 , 
Online,O
.,O
 , 
Hypophosphatasia,O
is,O
a,O
rare,O
inherited,O
disorder,O
characterized,O
by,O
defective,O
bone,O
mineralization,O
and,O
deficiency,O
of,O
serum,O
and,O
tissue,O
liver/,O
bone,O
/,O
kidney,O
tissue,B-Gene
alkaline,I-Gene
phosphatase,I-Gene
(,O
L,O
/,O
B,O
/,O
K,O
ALP,B-Gene
),I-Gene
activity,O
.,O
 , 
We,O
report,O
the,O
characterization,O
of,O
tissue,B-Gene
-,I-Gene
nonspecific,I-Gene
alkaline,I-Gene
phosphatase,I-Gene
(,B-Gene
TNSALP,I-Gene
),I-Gene
gene,O
mutations,O
in,O
a,O
series,O
of,O
9,O
families,O
affected,O
by,O
severe,O
hypophosphatasia,O
.,O
 , 
Fourteen,O
distinct,O
mutations,O
were,O
found,O
,,O
3,O
of,O
which,O
were,O
previously,O
reported,O
in,O
the,O
North,O
American,O
or,O
Japanese,O
populations,O
.,O
 , 
Seven,O
of,O
the,O
11,O
new,O
mutations,O
were,O
missense,O
mutations,O
(,B-SNP
M45L,I-SNP
,,I-SNP
R119H,B-SNP
,,I-SNP
G145V,B-SNP
,,I-SNP
C184Y,B-SNP
and,O
H154Y,B-SNP
,,I-SNP
D289V,B-SNP
,,I-SNP
E459,B-SNP
K,I-SNP
),I-SNP
,,O
the,O
four,O
others,O
were,O
2,O
single,O
nucleotide,O
deletions,O
(,B-SNP
544delG,I-SNP
and,O
1172delC,B-SNP
),I-SNP
,,O
a,O
mutation,O
affecting,O
donor,O
splice,O
site,O
(,B-SNP
862,I-SNP
+,I-SNP
5A,I-SNP
),I-SNP
and,O
a,O
nonsense,O
mutation,O
(,B-SNP
R411X,I-SNP
),I-SNP
.,O
 , 
#8477262
Identification,O
of,O
mutations,O
in,O
Danish,O
choroideremia,O
families,O
.,O
 , 
We,O
have,O
searched,O
for,O
mutations,O
in,O
the,O
choroideremia,B-Gene
gene,O
(,B-Gene
CHM,I-Gene
),I-Gene
in,O
patients,O
from,O
12,O
Danish,O
families,O
in,O
which,O
CHM,O
is,O
segregating,O
.,O
 , 
Employing,O
polymerase,O
chain,O
reaction,O
(,O
PCR,O
),O
,,O
single,O
strand,O
conformation,O
polymorphism,O
(,O
SSCP,O
),O
analysis,O
,,O
and,O
direct,O
DNA,O
sequencing,O
,,O
different,O
mutations,O
have,O
been,O
identified,O
in,O
6,O
patients,O
.,O
 , 
All,O
the,O
mutations,O
will,O
interfere,O
with,O
the,O
correct,O
translation,O
of,O
the,O
mRNA,O
predicting,O
a,O
truncated,O
protein,O
or,O
no,O
gene,O
product,O
at,O
all,O
.,O
 , 
#12673796
Detection,O
of,O
hotspot,O
mutations,O
and,O
polymorphisms,O
using,O
an,O
enhanced,O
PCR,O
-,O
RFLP,O
approach,O
.,O
 , 
Ethidium,O
gel,O
-,O
based,O
PCR,O
-,O
RFLP,O
is,O
widely,O
used,O
,,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
range,O
of,O
other,O
human,O
diseases,O
.,O
 , 
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
enhancement,O
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
introduction,O
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
increased,O
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
 , 
The,O
frequency,O
of,O
an,O
MSH2,B-Gene
missense,O
polymorphism,O
(,B-SNP
965G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
was,O
quantified,O
in,O
pooled,O
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
and,O
sheds,O
new,O
light,O
on,O
,,O
the,O
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
in,O
their,O
40s,O
or,O
50s,O
.,O
 , 
Preclinical,O
studies,O
of,O
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
in,O
knockout,O
mice,O
demonstrated,O
reduction,O
of,O
GL-3,B-Gene
in,O
tissues,O
and,O
plasma,O
,,O
providing,O
rationale,O
for,O
a,O
phase,O
1/2,O
clinical,O
trial,O
.,O
 , 
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
to,O
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
managed,O
conservatively,O
.,O
 , 
Of,O
15,O
patients,O
,,O
8,O
(,O
53,O
%,O
),O
developed,O
IgG,O
antibodies,O
to,O
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
for,O
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
.,O
 , 
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
will,O
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
were,O
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
yield,O
and,O
genotyping,O
performance,O
were,O
evaluated,O
using,O
genotypes,O
determined,O
from,O
gDNA,O
and,O
wgaDNA,O
using,O
the,O
AmpFlSTR,O
Identifiler,O
assay,O
and,O
N,O
=,O
49,O
 , 
TaqMan,O
SNP,O
assays,O
.,O
 , 
Short,O
tandem,O
repeat,O
(,O
STR,O
),O
and,O
SNP,O
genotyping,O
completion,O
and,O
concordance,O
rates,O
were,O
significantly,O
reduced,O
with,O
wgaDNA,O
from,O
all,O
WGA,O
methods,O
compared,O
with,O
gDNA,O
.,O
 , 
OmniPlex,O
wgaDNA,O
exhibited,O
a,O
greater,O
reduction,O
in,O
genotyping,O
performance,O
than,O
MDA,O
wgaDNA,O
.,O
 , 
Reduced,O
wgaDNA,O
genotyping,O
performance,O
was,O
due,O
to,O
allelic,O
(,O
all,O
protocols,O
),O
and,O
locus,O
(,O
OmniPlex,O
),O
amplification,O
bias,O
leading,O
to,O
heterozygote,O
and,O
locus,O
dropout,O
,,O
respectively,O
,,O
and,O
%,O
GC,O
sequence,O
content,O
(,O
%,O
GC,O
),O
was,O
significantly,O
correlated,O
with,O
TaqMan,O
assay,O
performance,O
.,O
 , 
Lymphoblast,O
wgaDNA,O
exhibited,O
higher,O
yield,O
(,O
OmniPlex,O
),O
,,O
buffy,O
coat,O
wgaDNA,O
exhibited,O
higher,O
STR,O
genotyping,O
completion,O
(,O
MDA,O
),O
,,O
whereas,O
mouthwash,O
wgaDNA,O
exhibited,O
higher,O
SNP,O
genotyping,O
discordance,O
(,O
MDA,O
),O
.,O
 , 
Genotyping,O
of,O
wgaDNA,O
generated,O
from,O
<,O
or,O
=,O
5,O
ng,O
gDNA,O
,,O
e.g.,O
,,O
from,O
archaeological,O
,,O
forensic,O
,,O
prenatal,O
diagnostic,O
,,O
or,O
pathology,O
samples,O
,,O
may,O
require,O
additional,O
genotyping,O
validation,O
with,O
gDNA,O
and/or,O
more,O
sophisticated,O
analysis,O
of,O
genotypes,O
incorporating,O
observed,O
reductions,O
in,O
genotyping,O
performance,O
.,O
 , 
#12080485
Mutations,O
in,O
two,O
genes,O
encoding,O
different,O
subunits,O
of,O
a,O
receptor,O
signaling,O
complex,O
result,O
in,O
an,O
identical,O
disease,O
phenotype,O
.,O
 , 
Polycystic,O
lipomembranous,O
osteodysplasia,O
with,O
sclerosing,O
leukoencephalopathy,O
(,O
PLOSL,O
),O
,,O
also,O
known,O
as,O
",O
Nasu,O
-,O
Hakola,O
disease,O
,,O
",O
is,O
a,O
globally,O
distributed,O
recessively,O
inherited,O
disease,O
leading,O
to,O
death,O
during,O
the,O
5th,O
decade,O
of,O
life,O
and,O
is,O
characterized,O
by,O
early,O
-,O
onset,O
progressive,O
dementia,O
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
(,B-Gene
DAP12,I-Gene
),I-Gene
,,O
which,O
codes,O
for,O
a,O
membrane,O
receptor,O
component,O
in,O
natural,O
-,O
killer,O
and,O
myeloid,O
cells,O
,,O
and,O
also,O
have,O
identified,O
genetic,O
heterogeneity,O
in,O
PLOSL,O
,,O
with,O
some,O
patients,O
carrying,O
no,O
mutations,O
in,O
TYROBP,B-Gene
.,I-Gene
 , 
Here,O
we,O
complete,O
the,O
molecular,O
pathology,O
of,O
PLOSL,O
by,O
identifying,O
TREM2,B-Gene
as,O
the,O
second,O
PLOSL,O
gene,O
.,O
 , 
TREM2,B-Gene
forms,O
a,O
receptor,O
signaling,O
complex,O
with,O
TYROBP,B-Gene
and,O
triggers,O
activation,O
of,O
the,O
immune,O
responses,O
in,O
macrophages,O
and,O
dendritic,O
cells,O
.,O
 , 
Patients,O
with,O
PLOSL,O
have,O
no,O
defects,O
in,O
cell,O
-,O
mediated,O
immunity,O
,,O
suggesting,O
a,O
remarkable,O
capacity,O
of,O
the,O
human,O
immune,O
system,O
to,O
compensate,O
for,O
the,O
inactive,O
TYROBP,B-Gene
-,I-Gene
mediated,O
activation,O
pathway,O
.,O
 , 
Our,O
data,O
imply,O
that,O
the,O
TYROBP,B-Gene
-,I-Gene
mediated,O
signaling,O
pathway,O
plays,O
a,O
significant,O
role,O
in,O
human,O
brain,O
and,O
bone,O
tissue,O
and,O
provide,O
an,O
interesting,O
example,O
of,O
how,O
mutations,O
in,O
two,O
different,O
subunits,O
of,O
a,O
multisubunit,O
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
requires,O
correct,O
specification,O
of,O
the,O
relationships,O
of,O
the,O
pairs,O
.,O
 , 
For,O
example,O
,,O
within,O
a,O
sibship,O
,,O
presumed,O
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
and,O
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
of,O
the,O
beta,B-Gene
-,I-Gene
globin,I-Gene
gene,O
of,O
sickle,O
cell,O
anemia,O
patients,O
with,O
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
across,O
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
heterogeneity,O
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
and,O
matrix,B-Gene
metallopeptidase,I-Gene
12,I-Gene
(,B-Gene
MMP12,I-Gene
),I-Gene
(,O
11q22.3,O
),O
genes,O
were,O
specific,O
to,O
MPNSTs,O
.,O
 , 
Pathway,O
analysis,O
revealed,O
the,O
MPNST,O
-,O
specific,O
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
whereas,O
wound,O
healing,O
,,O
cell,O
migration,O
,,O
and,O
invasiveness,O
were,O
reduced,O
,,O
consistent,O
with,O
a,O
role,O
for,O
these,O
Rho,O
-,O
GTPase,O
pathway,O
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
>,I-SNP
T,I-SNP
(,B-SNP
p.,I-SNP
C93F,I-SNP
),I-SNP
,,O
and,O
(,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
and,O
mammalian,O
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
is,O
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
gene,O
causes,O
infantile,O
-,O
onset,O
Sandhoff,O
disease,O
.,O
 , 
#12958705
Genomewide,O
linkage,O
and,O
linkage,O
disequilibrium,O
analyses,O
identify,O
COL6A1,B-Gene
,,I-Gene
on,O
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
was,O
detected,O
on,O
chromosomes,O
1p,O
,,O
6p,O
,,O
11q,O
,,O
14q,O
,,O
16q,O
,,O
and,O
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
therefore,O
,,O
the,O
linkage,O
region,O
was,O
extensively,O
investigated,O
for,O
linkage,O
disequilibrium,O
with,O
single,O
-,O
nucleotide,O
polymorphisms,O
(,O
SNPs,O
),O
covering,O
20,O
Mb,O
.,O
 , 
One,O
hundred,O
fifty,O
positional,O
candidate,O
genes,O
lie,O
in,O
the,O
region,O
,,O
and,O
600,O
gene,O
-,O
based,O
SNPs,O
were,O
genotyped,O
.,O
 , 
There,O
were,O
positive,O
allelic,O
associations,O
with,O
seven,O
genes,O
(,O
P<.01,O
),O
in,O
280,O
patients,O
and,O
210,O
controls,O
,,O
and,O
four,O
of,O
the,O
seven,O
genes,O
were,O
clustered,O
within,O
a,O
region,O
of,O
750,O
kb,O
,,O
approximately,O
1.2,O
Mb,O
telomeric,O
to,O
D21S1903,O
.,O
 , 
Extensive,O
linkage,O
disequilibrium,O
and,O
association,O
studies,O
of,O
the,O
four,O
genes,O
indicated,O
that,O
SNPs,O
in,O
the,O
collagen,B-Gene
6A1,I-Gene
gene,O
(,B-Gene
COL6A1,I-Gene
),I-Gene
were,O
strongly,O
associated,O
with,O
OPLL,O
(,O
P=.000003,O
for,O
the,O
SNP,O
in,O
intron,O
32,O
 , 
[,O
-29,O
],O
),O
.,O
 , 
Haplotype,O
analysis,O
with,O
three,O
SNPs,O
in,O
COL6A1,B-Gene
gave,O
a,O
single,O
-,O
point,O
P,O
value,O
of.0000007,O
.,O
 , 
Identification,O
of,O
the,O
locus,O
of,O
susceptibility,O
to,O
OPLL,O
by,O
genomewide,O
linkage,O
and,O
linkage,O
disequilibrium,O
studies,O
permits,O
us,O
to,O
investigate,O
the,O
pathogenesis,O
of,O
the,O
disease,O
,,O
which,O
may,O
lead,O
to,O
the,O
development,O
of,O
novel,O
therapeutic,O
tools,O
.,O
 , 
#14658095
Linkage,O
at,O
12q24,O
with,O
systemic,O
lupus,O
erythematosus,O
(,O
SLE,O
),O
is,O
established,O
and,O
confirmed,O
in,O
Hispanic,O
and,O
European,O
American,O
families,O
.,O
 , 
Systemic,O
lupus,O
erythematosus,O
(,O
SLE,O
),O
is,O
a,O
chronic,O
,,O
complex,O
,,O
and,O
systemic,O
human,O
autoimmune,O
disease,O
,,O
with,O
both,O
an,O
environmental,O
component,O
and,O
a,O
heritable,O
predisposition,O
.,O
 , 
Clinical,O
studies,O
,,O
reinforced,O
by,O
epidemiology,O
and,O
genetics,O
,,O
show,O
impressive,O
variation,O
in,O
disease,O
severity,O
,,O
expression,O
,,O
prevalence,O
,,O
and,O
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
using,O
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
suggested,O
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
 , 
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
a,O
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
in,O
a,O
sporadically,O
occurring,O
perinatal,O
lethal,O
skeletal,O
dysplasia,O
characterized,O
by,O
poor,O
mineralization,O
of,O
the,O
calvarium,O
,,O
craniosynostosis,O
,,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
diseased,O
chondrocytes,O
and,O
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
and,O
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
dominant,O
hypercholesterolemia,O
(,O
ADH,O
),O
is,O
a,O
frequent,O
(,O
1/500,O
),O
monogenic,O
inherited,O
disorder,O
characterized,O
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
and,O
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
),I-Gene
gene,O
that,O
encodes,O
Narc-1,B-Gene
(,B-Gene
neural,I-Gene
apoptosis,I-Gene
-,I-Gene
regulated,I-Gene
convertase,I-Gene
1,I-Gene
),I-Gene
.,O
 , 
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
and,O
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
one,O
Asian,O
and,O
three,O
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
the,O
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
base,O
substitution,O
in,O
the,O
promoter,O
associated,O
with,O
the,O
human,O
haptoglobin,B-Gene
2,I-Gene
-,I-Gene
1,I-Gene
modified,O
phenotype,O
decreases,O
transcriptional,O
activity,O
and,O
responsiveness,O
to,O
interleukin-6,B-Gene
in,O
human,O
hepatoma,O
cells,O
.,O
 , 
An,O
A,B-SNP
-,I-SNP
to,I-SNP
-,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
the,O
promoter,O
region,O
of,O
the,O
human,O
haptoglobin,B-Gene
gene,O
(,B-Gene
Hp,I-Gene
),I-Gene
has,O
been,O
shown,O
to,O
be,O
strongly,O
associated,O
with,O
the,O
haptoglobin,B-Gene
2,I-Gene
-,I-Gene
1,I-Gene
modified,O
(,O
Hp2,O
-,O
1mod,O
),O
phenotype,O
.,O
 , 
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
relative,O
to,O
the,O
Hp1,B-Gene
allele,O
in,O
individuals,O
with,O
the,O
Hp2,O
-,O
1mod,O
phenotype,O
,,O
we,O
used,O
the,O
chloramphenicol,O
acetyl,O
transferase,O
(,O
CAT,O
),O
expression,O
system,O
to,O
evaluate,O
promoter,O
function,O
.,O
 , 
In,O
HepG2,O
cells,O
,,O
which,O
normally,O
express,O
their,O
endogenous,O
haptoglobin,O
genes,O
,,O
CAT,O
plasmid,O
constructs,O
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
 , 
The,O
-61C,O
substitution,O
also,O
rendered,O
the,O
construct,O
unresponsive,O
to,O
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
 , 
In,O
addition,O
,,O
two,O
base,O
substitutions,O
,,O
T,B-SNP
to,I-SNP
A,I-SNP
and,I-SNP
A,I-SNP
to,I-SNP
G,I-SNP
,,I-SNP
at,I-SNP
positions,I-SNP
-104,I-SNP
and,I-SNP
-55,I-SNP
G,I-SNP
,,I-SNP
respectively,I-SNP
,,I-SNP
in,O
the,O
promoter,O
region,O
of,O
the,O
Hp1,B-Gene
allele,O
,,O
are,O
also,O
associated,O
with,O
the,O
Hp2,O
-,O
1mod,O
phenotype,O
.,O
 , 
CAT,O
constructs,O
with,O
both,O
substitutions,O
(,B-SNP
-104A-55,I-SNP
G,I-SNP
),I-SNP
and,O
with,O
one,O
substitution,O
(,O
-55,O
G,O
),O
showed,O
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
with,O
the,O
Hp,O
control,O
construct,O
.,O
 , 
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
the,O
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
about,O
cause,O
,,O
pathogenesis,O
,,O
and,O
manifestations,O
of,O
hereditary,O
metabolic,O
diseases,O
puts,O
them,O
among,O
the,O
best,O
known,O
of,O
all,O
human,O
diseases,O
.,O
 , 
On,O
the,O
other,O
hand,O
,,O
outcomes,O
of,O
treatment,O
are,O
cause,O
for,O
uncertainty,O
and,O
concern,O
.,O
 , 
In,O
1985,O
,,O
Hayes,O
et,O
al,O
.,O
analyzed,O
efficacy,O
of,O
treatment,O
up,O
to,O
1983,O
in,O
65,O
of,O
these,O
diseases,O
selected,O
randomly,O
from,O
the,O
McKusick,O
catalogs,O
.,O
 , 
Disease,O
scores,O
were,O
calculated,O
for,O
seven,O
parameters,O
:,O
longevity,O
;,O
reproductive,O
capability,O
;,O
somatic,O
and,O
cognitive,O
development,O
;,O
and,O
handicaps,O
affecting,O
schooling,O
,,O
work,O
,,O
and,O
cosmetic,O
appearance,O
.,O
 , 
Scores,O
of,O
the,O
untreated,O
and,O
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
were,O
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
the,O
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
advances,O
are,O
attributable,O
to,O
greater,O
success,O
with,O
organ,O
and,O
tissue,O
transplantation,O
,,O
better,O
pharmacotherapy,O
,,O
and,O
better,O
support,O
systems,O
.,O
 , 
Restoration,O
of,O
normal,O
homeostasis,O
,,O
the,O
key,O
to,O
successful,O
treatment,O
,,O
remains,O
an,O
elusive,O
challenge,O
and,O
is,O
a,O
logical,O
,,O
major,O
focus,O
for,O
research,O
in,O
human,O
genetics,O
.,O
 , 
#18950739
The,O
Human,O
Phenotype,O
Ontology,O
:,O
a,O
tool,O
for,O
annotating,O
and,O
analyzing,O
human,O
hereditary,O
disease,O
.,O
 , 
There,O
are,O
many,O
thousands,O
of,O
hereditary,O
diseases,O
in,O
humans,O
,,O
each,O
of,O
which,O
has,O
a,O
specific,O
combination,O
of,O
phenotypic,O
features,O
,,O
but,O
computational,O
analysis,O
of,O
phenotypic,O
data,O
has,O
been,O
hampered,O
by,O
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
with,O
over,O
8000,O
terms,O
representing,O
individual,O
phenotypic,O
anomalies,O
and,O
have,O
annotated,O
all,O
clinical,O
entries,O
in,O
Online,O
Mendelian,O
Inheritance,O
in,O
Man,O
with,O
the,O
terms,O
of,O
the,O
HPO,O
.,O
 , 
We,O
show,O
that,O
the,O
HPO,O
is,O
able,O
to,O
capture,O
phenotypic,O
similarities,O
between,O
diseases,O
in,O
a,O
useful,O
and,O
highly,O
significant,O
fashion,O
.,O
 , 
#22226083
Transient,O
infantile,O
hypertriglyceridemia,O
,,O
fatty,O
liver,O
,,O
and,O
hepatic,O
fibrosis,O
caused,O
by,O
mutated,O
GPD1,B-Gene
,,I-Gene
encoding,O
glycerol-3,B-Gene
-,I-Gene
phosphate,I-Gene
dehydrogenase,I-Gene
1,I-Gene
.,I-Gene
 , 
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
of,O
cases,O
.,O
 , 
Investigation,O
of,O
monogenic,O
dyslipidemias,O
has,O
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
encodes,O
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
secretion,O
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
report,O
from,O
the,O
Cystic,O
Fibrosis,O
Genetic,O
Analysis,O
Consortium,O
.,O
 , 
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
in,O
congenital,O
chloride,O
diarrhea,O
.,O
 , 
Congenital,O
chloride,O
diarrhea,O
(,O
CLD,O
),O
is,O
an,O
autosomal,O
recessive,O
disorder,O
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
,,I-Gene
member,I-Gene
3,I-Gene
gene,I-Gene
(,B-Gene
SLC26A3,I-Gene
,,I-Gene
previously,O
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
and,O
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
including,O
two,O
missense,O
mutations,O
(,B-SNP
S206P,I-SNP
,,I-SNP
D468V,B-SNP
),I-SNP
,,O
two,O
splicing,O
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
nonsense,O
mutation,O
(,B-SNP
Q436X,I-SNP
),I-SNP
,,O
one,O
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
previously,O
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
the,O
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
may,O
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
 , 
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
 , 
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
 , 
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
of,O
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
based,O
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
from,O
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
previously,O
mapped,O
to,O
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
slow,I-Gene
),I-Gene
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
),I-Gene
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
on,O
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
20,O
Dusun,O
children,O
from,O
the,O
East,O
Malaysian,O
state,O
of,O
Sabah,O
(,O
North,O
Borneo,O
),O
with,O
a,O
severe,O
beta,O
-,O
thalassemia,O
major,O
phenotype,O
,,O
using,O
a,O
combination,O
of,O
Southern,O
analysis,O
,,O
polymerase,O
chain,O
reaction,O
analysis,O
and,O
direct,O
sequencing,O
.,O
 , 
We,O
found,O
the,O
children,O
to,O
be,O
homozygous,O
for,O
a,O
large,O
deletion,O
,,O
which,O
has,O
a,O
5,O
',O
breakpoint,O
at,O
position,O
-4279,O
from,O
the,O
cap,O
site,O
of,O
the,O
beta,O
-,O
globin,O
gene,O
(,O
HBB,O
),O
with,O
the,O
3,O
',O
breakpoint,O
located,O
in,O
a,O
L1,O
family,O
of,O
repetitive,O
sequences,O
at,O
an,O
unknown,O
distance,O
from,O
the,O
beta,B-Gene
-,I-Gene
globin,I-Gene
gene,O
.,O
 , 
This,O
was,O
similar,O
to,O
a,O
recent,O
finding,O
of,O
a,O
large,O
deletion,O
causing,O
beta,O
-,O
thalassemia,O
first,O
described,O
in,O
unrelated,O
beta,O
-,O
thalassemia,O
heterozygotes,O
of,O
Filipino,O
descent,O
.,O
 , 
This,O
report,O
describes,O
the,O
first,O
20,O
families,O
with,O
homozygosity,O
of,O
the,O
deletion,O
causing,O
a,O
severe,O
phenotype,O
.,O
 , 
It,O
provides,O
the,O
first,O
information,O
on,O
the,O
molecular,O
epidemiology,O
of,O
beta,O
-,O
thalassemia,O
in,O
Sabah,O
.,O
 , 
This,O
finding,O
has,O
implications,O
for,O
the,O
population,O
genetics,O
and,O
preventative,O
strategies,O
for,O
beta,O
-,O
thalassemia,O
major,O
for,O
nearly,O
300,O
million,O
individuals,O
in,O
South,O
-,O
East,O
Asia,O
.,O
 , 
#17924341
Fine,O
mapping,O
versus,O
replication,O
in,O
whole,O
-,O
genome,O
association,O
studies,O
.,O
 , 
Association,O
replication,O
studies,O
have,O
a,O
poor,O
track,O
record,O
and,O
,,O
even,O
when,O
successful,O
,,O
often,O
claim,O
association,O
with,O
different,O
markers,O
,,O
alleles,O
,,O
and,O
phenotypes,O
than,O
those,O
reported,O
in,O
the,O
primary,O
study,O
.,O
 , 
It,O
is,O
unknown,O
whether,O
these,O
outcomes,O
reflect,O
genuine,O
associations,O
or,O
false,O
-,O
positive,O
results,O
.,O
 , 
A,O
greater,O
understanding,O
of,O
these,O
observations,O
is,O
essential,O
for,O
genomewide,O
association,O
(,O
GWA,O
),O
studies,O
,,O
since,O
they,O
have,O
the,O
potential,O
to,O
identify,O
multiple,O
new,O
associations,O
that,O
that,O
will,O
require,O
external,O
validation,O
.,O
 , 
Theoretically,O
,,O
a,O
repeat,O
association,O
with,O
precisely,O
the,O
same,O
variant,O
in,O
an,O
independent,O
sample,O
is,O
the,O
gold,O
standard,O
for,O
replication,O
,,O
but,O
testing,O
additional,O
variants,O
is,O
commonplace,O
in,O
replication,O
studies,O
.,O
 , 
Finding,O
different,O
associated,O
SNPs,O
within,O
the,O
same,O
gene,O
or,O
region,O
as,O
that,O
originally,O
identified,O
is,O
often,O
reported,O
as,O
confirmatory,O
evidence,O
.,O
 , 
Here,O
,,O
we,O
compare,O
the,O
probability,O
of,O
replicating,O
a,O
gene,O
or,O
region,O
under,O
two,O
commonly,O
used,O
marker,O
-,O
selection,O
strategies,O
:,O
an,O
",O
exact,O
",O
approach,O
that,O
involves,O
only,O
the,O
originally,O
significant,O
markers,O
and,O
a,O
",O
local,O
",O
approach,O
that,O
involves,O
both,O
the,O
originally,O
significant,O
markers,O
and,O
others,O
in,O
the,O
same,O
region,O
.,O
 , 
When,O
a,O
region,O
of,O
high,O
intermarker,O
linkage,O
disequilibrium,O
is,O
tested,O
to,O
replicate,O
an,O
initial,O
finding,O
that,O
is,O
only,O
weak,O
association,O
with,O
disease,O
,,O
the,O
local,O
approach,O
is,O
a,O
good,O
strategy,O
.,O
 , 
Otherwise,O
,,O
the,O
most,O
powerful,O
and,O
efficient,O
strategy,O
for,O
replication,O
involves,O
testing,O
only,O
the,O
initially,O
identified,O
variants,O
.,O
 , 
Association,O
with,O
a,O
marker,O
other,O
than,O
that,O
originally,O
identified,O
can,O
occur,O
frequently,O
,,O
even,O
in,O
the,O
presence,O
of,O
real,O
effects,O
in,O
a,O
low,O
-,O
powered,O
replication,O
study,O
,,O
and,O
instances,O
of,O
such,O
association,O
increase,O
as,O
the,O
number,O
of,O
included,O
variants,O
increases,O
.,O
 , 
Our,O
results,O
provide,O
a,O
basis,O
for,O
the,O
design,O
and,O
interpretation,O
of,O
GWA,O
replication,O
studies,O
and,O
point,O
to,O
the,O
importance,O
of,O
a,O
clear,O
distinction,O
between,O
fine,O
mapping,O
and,O
replication,O
after,O
GWA,O
.,O
 , 
#20021999
Loss,O
-,O
of,O
-,O
function,O
mutations,O
in,O
the,O
PRPS1,B-Gene
gene,O
cause,O
a,O
type,O
of,O
nonsyndromic,O
X,O
-,O
linked,O
sensorineural,O
deafness,O
,,O
DFN2,O
.,O
 , 
We,O
report,O
a,O
large,O
Chinese,O
family,O
with,O
X,O
-,O
linked,O
postlingual,O
nonsyndromic,O
hearing,O
impairment,O
in,O
which,O
the,O
critical,O
linkage,O
interval,O
spans,O
a,O
genetic,O
distance,O
of,O
5.41,O
cM,O
and,O
a,O
physical,O
distance,O
of,O
15.1,O
Mb,O
that,O
overlaps,O
the,O
DFN2,O
locus,O
.,O
 , 
Mutation,O
screening,O
of,O
the,O
PRPS1,B-Gene
gene,O
in,O
this,O
family,O
and,O
in,O
the,O
three,O
previously,O
reported,O
DFN2,O
families,O
identified,O
four,O
different,O
missense,O
mutations,O
in,O
PRPS1,B-Gene
.,I-Gene
 , 
These,O
mutations,O
result,O
in,O
a,O
loss,O
of,O
phosphoribosyl,O
pyrophosphate,O
(,O
PRPP,O
),O
synthetase,O
1,O
activity,O
,,O
as,O
was,O
shown,O
in,O
silico,O
by,O
structural,O
analysis,O
and,O
was,O
shown,O
in,O
vitro,O
by,O
enzymatic,O
activity,O
assays,O
in,O
erythrocytes,O
and,O
fibroblasts,O
from,O
patients,O
.,O
 , 
By,O
in,O
situ,O
hybridization,O
,,O
we,O
demonstrate,O
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
and,O
postnatal,O
expression,O
in,O
the,O
spiral,O
ganglion,O
.,O
 , 
Being,O
the,O
second,O
identified,O
gene,O
associated,O
with,O
X,O
-,O
linked,O
nonsyndromic,O
deafness,O
,,O
PRPS1,B-Gene
will,O
be,O
a,O
good,O
candidate,O
gene,O
for,O
genetic,O
testing,O
for,O
X,O
-,O
linked,O
nonsyndromic,O
hearing,O
loss,O
.,O
 , 
#14610717
Allelic,O
heterogeneity,O
in,O
LINE-1,O
retrotransposition,O
activity,O
.,O
 , 
De,O
novo,O
LINE-1,O
(,O
long,O
interspersed,O
element-1,O
,,O
or,O
L1,O
),O
retrotransposition,O
events,O
are,O
responsible,O
for,O
approximately,O
1/1,000,O
disease,O
-,O
causing,O
mutations,O
in,O
humans,O
.,O
 , 
Previously,O
,,O
L1.2,O
was,O
identified,O
as,O
the,O
likely,O
progenitor,O
of,O
a,O
mutagenic,O
insertion,O
in,O
the,O
factor,O
VIII,O
gene,O
in,O
a,O
patient,O
with,O
hemophilia,O
A.,O
It,O
subsequently,O
was,O
shown,O
to,O
be,O
one,O
of,O
a,O
small,O
number,O
of,O
active,O
L1s,O
in,O
the,O
human,O
genome,O
.,O
 , 
Here,O
,,O
we,O
demonstrate,O
that,O
L1.2,O
is,O
present,O
at,O
an,O
intermediate,O
insertion,O
allele,O
frequency,O
in,O
worldwide,O
human,O
populations,O
and,O
that,O
common,O
alleles,O
(,O
L1.2A,O
and,O
L1.2B,O
),O
exhibit,O
an,O
approximately,O
16,O
-,O
fold,O
difference,O
in,O
their,O
ability,O
to,O
retrotranspose,O
in,O
cultured,O
human,O
HeLa,O
cells,O
.,O
 , 
Chimera,O
analysis,O
revealed,O
that,O
two,O
amino,O
acid,O
substitutions,O
(,B-SNP
S1259L,I-SNP
and,O
I1220,B-SNP
M,I-SNP
),I-SNP
downstream,O
of,O
the,O
conserved,O
cysteine,O
-,O
rich,O
motif,O
in,O
L1,O
open,O
reading,O
frame,O
2,O
are,O
largely,O
responsible,O
for,O
the,O
observed,O
reduction,O
in,O
L1.2A,O
retrotransposition,O
efficiency,O
.,O
 , 
Thus,O
,,O
common,O
L1,O
alleles,O
can,O
vary,O
widely,O
in,O
their,O
retrotransposition,O
potential,O
.,O
 , 
We,O
propose,O
that,O
such,O
allelic,O
heterogeneity,O
can,O
influence,O
the,O
potential,O
L1,O
mutational,O
load,O
present,O
in,O
an,O
individual,O
genome,O
.,O
 , 
#20466092
The,O
number,O
of,O
markers,O
in,O
the,O
HapMap,O
project,O
:,O
some,O
notes,O
on,O
chi,O
-,O
square,O
and,O
exact,O
tests,O
for,O
Hardy,O
-,O
Weinberg,O
equilibrium,O
.,O
 , 
#19012875
Divergence,O
between,O
human,O
populations,O
estimated,O
from,O
linkage,O
disequilibrium,O
.,O
 , 
Observed,O
linkage,O
disequilibrium,O
(,O
LD,O
),O
between,O
genetic,O
markers,O
in,O
different,O
populations,O
descended,O
independently,O
from,O
a,O
common,O
ancestral,O
population,O
can,O
be,O
used,O
to,O
estimate,O
their,O
absolute,O
time,O
of,O
divergence,O
,,O
because,O
the,O
correlation,O
of,O
LD,O
between,O
populations,O
will,O
be,O
reduced,O
each,O
generation,O
by,O
an,O
amount,O
that,O
,,O
approximately,O
,,O
depends,O
only,O
on,O
the,O
recombination,O
rate,O
between,O
markers,O
.,O
 , 
Although,O
drift,O
leads,O
to,O
divergence,O
in,O
allele,O
frequencies,O
,,O
it,O
has,O
less,O
effect,O
on,O
divergence,O
in,O
LD,O
values,O
.,O
 , 
We,O
derived,O
the,O
relationship,O
between,O
LD,O
and,O
time,O
of,O
divergence,O
and,O
verified,O
it,O
with,O
coalescent,O
simulations,O
.,O
 , 
We,O
then,O
used,O
HapMap,O
Phase,O
II,O
data,O
to,O
estimate,O
time,O
of,O
divergence,O
between,O
human,O
populations,O
.,O
 , 
Summed,O
over,O
large,O
numbers,O
of,O
pairs,O
of,O
loci,O
,,O
we,O
find,O
a,O
positive,O
correlation,O
of,O
LD,O
between,O
African,O
and,O
non,O
-,O
African,O
populations,O
at,O
levels,O
of,O
up,O
to,O
approximately,O
0.3,O
cM.,O
 , 
We,O
estimate,O
that,O
the,O
observed,O
correlation,O
of,O
LD,O
is,O
consistent,O
with,O
an,O
effective,O
separation,O
time,O
of,O
approximately,O
1,000,O
generations,O
or,O
approximately,O
25,000,O
years,O
before,O
present,O
.,O
 , 
The,O
most,O
likely,O
explanation,O
for,O
such,O
relatively,O
low,O
separation,O
times,O
is,O
the,O
existence,O
of,O
substantial,O
levels,O
of,O
migration,O
between,O
populations,O
after,O
the,O
initial,O
separation,O
.,O
 , 
Theory,O
and,O
results,O
from,O
coalescent,O
simulations,O
confirm,O
that,O
low,O
levels,O
of,O
migration,O
can,O
lead,O
to,O
a,O
downward,O
bias,O
in,O
the,O
estimate,O
of,O
separation,O
time,O
.,O
 , 
#10090915
Prevalence,O
of,O
Bloom,O
syndrome,O
heterozygotes,O
among,O
Ashkenazi,O
Jews,O
.,O
 , 
#15359380
Genetic,O
variation,O
in,O
radiation,O
-,O
induced,O
expression,O
phenotypes,O
.,O
 , 
Studies,O
have,O
demonstrated,O
that,O
natural,O
variation,O
in,O
the,O
expression,O
level,O
of,O
genes,O
at,O
baseline,O
is,O
extensive,O
,,O
and,O
the,O
determinants,O
of,O
this,O
variation,O
can,O
be,O
mapped,O
by,O
a,O
genetic,O
-,O
linkage,O
approach,O
.,O
 , 
In,O
this,O
study,O
,,O
we,O
used,O
lymphoblastoid,O
cells,O
to,O
explore,O
the,O
variation,O
in,O
radiation,O
-,O
induced,O
transcriptional,O
changes,O
.,O
 , 
We,O
found,O
that,O
,,O
among,O
normal,O
individuals,O
,,O
there,O
is,O
extensive,O
variation,O
in,O
transcriptional,O
response,O
to,O
radiation,O
exposure,O
.,O
 , 
By,O
studying,O
monozygotic,O
twins,O
,,O
we,O
demonstrated,O
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
variation,O
in,O
the,O
expression,O
level,O
of,O
several,O
genes,O
,,O
including,O
the,O
ferredoxin,B-Gene
reductase,I-Gene
gene,O
(,B-Gene
FDXR,I-Gene
),I-Gene
and,O
the,O
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
during,O
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
presence,O
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
of,O
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
of,O
the,O
normal,O
ferrochelatase,O
allele,O
.,O
 , 
Erythropoietic,O
protoporphyria,O
(,O
EPP,O
),O
is,O
a,O
monogenic,O
inherited,O
disorder,O
of,O
the,O
heme,O
biosynthetic,O
pathway,O
due,O
to,O
ferrochelatase,O
(,O
FC,O
),O
deficiency,O
.,O
 , 
EPP,O
is,O
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
10,O
consensus,O
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
and,O
a,O
new,O
intragenic,O
dimorphism,O
(,B-SNP
1520,I-SNP
C,I-SNP
/,I-SNP
T,I-SNP
),I-SNP
.,O
 , 
mRNAs,O
transcribed,O
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
and,O
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
using,O
linkage,O
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
decomposition,O
of,O
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
also,O
modify,O
Clayton,O
's,O
",O
haplotype,O
tagging,O
SNP,O
",O
selection,O
method,O
,,O
which,O
utilizes,O
haplotype,O
information,O
.,O
 , 
For,O
both,O
methods,O
,,O
we,O
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
number,O
of,O
individuals,O
for,O
an,O
initial,O
set,O
of,O
SNPs,O
and,O
selection,O
of,O
an,O
optimum,O
subset,O
of,O
SNPs,O
that,O
could,O
be,O
efficiently,O
genotyped,O
on,O
larger,O
numbers,O
of,O
samples,O
while,O
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
 , 
When,O
applied,O
to,O
experimental,O
data,O
sets,O
,,O
both,O
procedures,O
were,O
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
almost,O
identical,O
before,O
and,O
after,O
marker,O
selection,O
.,O
 , 
#10775524
Identification,O
of,O
uniparental,O
disomy,O
following,O
prenatal,O
detection,O
of,O
Robertsonian,O
translocations,O
and,O
isochromosomes,O
.,O
 , 
Rearrangements,O
of,O
the,O
acrocentric,O
chromosomes,O
(,O
Robertsonian,O
translocations,O
and,O
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
of,O
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
 , 
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
to,O
the,O
identification,O
of,O
four,O
mutants,O
(,B-SNP
R304W,I-SNP
,,I-SNP
I177N,B-SNP
,,I-SNP
K175,B-SNP
-,I-SNP
D176del,I-SNP
,,I-SNP
L263fsX286,B-SNP
),I-SNP
and,O
two,O
novel,O
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
American,O
,,O
and,O
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
and,O
consequent,O
ventricular,O
arrhythmias,O
.,O
 , 
Heterozygous,O
mutations,O
in,O
PKP2,B-Gene
encoding,O
plakophilin-2,B-Gene
have,O
previously,O
been,O
reported,O
to,O
cause,O
dominant,O
ARVD,O
with,O
reduced,O
penetrance,O
.,O
 , 
We,O
report,O
the,O
first,O
case,O
of,O
recessive,O
ARVD,O
caused,O
by,O
mutations,O
in,O
PKP2,B-Gene
.,I-Gene
 , 
Candidate,O
gene,O
analysis,O
in,O
a,O
typical,O
proband,O
with,O
this,O
disorder,O
identified,O
a,O
novel,O
homozygous,O
mutation,O
in,O
PKP2,B-Gene
(,B-SNP
c.[2484C,I-SNP
>,I-SNP
T]+[2484C,I-SNP
>,I-SNP
T,I-SNP
],I-SNP
),O
,,O
which,O
is,O
predicted,O
to,O
be,O
translationally,O
silent,O
(,B-SNP
p.,I-SNP
Gly828,I-SNP
),I-SNP
.,O
 , 
Analysis,O
of,O
the,O
proband,O
's,O
mRNA,O
,,O
however,O
,,O
shows,O
that,O
this,O
mutation,O
causes,O
predominantly,O
cryptic,O
splicing,O
,,O
with,O
a,O
7,O
-,O
nucleotide,O
deletion,O
in,O
exon,O
12,O
.,O
 , 
The,O
ensuing,O
frame,O
shift,O
disrupts,O
the,O
last,O
54,O
amino,O
acids,O
of,O
plakophilin-2,O
and,O
extends,O
the,O
open,O
reading,O
frame,O
by,O
145,O
nucleotides,O
(,O
48,O
amino,O
acids,O
),O
into,O
the,O
3,O
',O
untranslated,O
region,O
.,O
 , 
Haplotype,O
analysis,O
demonstrates,O
the,O
absence,O
of,O
remote,O
consanguinity,O
.,O
 , 
Heterozygous,O
family,O
members,O
produce,O
approximately,O
60,O
%,O
of,O
properly,O
spliced,O
PKP2,B-Gene
and,O
do,O
not,O
have,O
manifestations,O
of,O
ARVD,O
.,O
 , 
Further,O
analysis,O
of,O
PKP2,B-Gene
mRNA,O
sequence,O
revealed,O
two,O
additional,O
alternatively,O
spliced,O
transcripts,O
.,O
 , 
The,O
possibility,O
of,O
cryptic,O
or,O
alternative,O
splicing,O
should,O
be,O
considered,O
with,O
identification,O
of,O
apparently,O
synonymous,O
nucleotide,O
substitutions,O
in,O
this,O
gene,O
.,O
 , 
#8116620
Identification,O
of,O
internal,O
variation,O
in,O
the,O
pseudoautosomal,O
VNTR,O
DXYS17,O
,,O
with,O
nonrandom,O
distribution,O
of,O
the,O
alleles,O
on,O
the,O
X,O
and,O
the,O
Y,O
chromosomes,O
.,O
 , 
The,O
PCR,O
technique,O
was,O
used,O
to,O
analyze,O
the,O
DXYS17,O
locus,O
in,O
the,O
pseudoautosomal,O
region,O
of,O
the,O
X,O
and,O
the,O
Y,O
chromosomes,O
.,O
 , 
Analysis,O
on,O
an,O
automated,O
DNA,O
sequencer,O
allowed,O
for,O
sensitive,O
and,O
highly,O
accurate,O
typing,O
of,O
16,O
different,O
alleles,O
with,O
a,O
size,O
between,O
480,O
and,O
1,100,O
bp,O
.,O
 , 
Two,O
DXYS17,O
alleles,O
migrated,O
with,O
the,O
same,O
size,O
on,O
agarose,O
or,O
denaturing,O
polyacrylamide,O
gels,O
 , 
but,O
with,O
different,O
mobilities,O
on,O
nondenaturing,O
polyacrylamide,O
gels,O
.,O
 , 
Sequence,O
analysis,O
showed,O
that,O
,,O
while,O
an,O
identical,O
number,O
of,O
repeats,O
were,O
present,O
in,O
both,O
alleles,O
,,O
differences,O
in,O
the,O
composition,O
of,O
the,O
units,O
were,O
observed,O
.,O
 , 
The,O
origin,O
of,O
these,O
differences,O
was,O
found,O
in,O
the,O
28-,O
and,O
33,O
-,O
bp,O
units,O
,,O
which,O
only,O
had,O
a,O
specific,O
repeat,O
pattern,O
at,O
the,O
5,O
',O
and,O
3,O
',O
ends,O
of,O
the,O
region,O
.,O
 , 
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
under,O
Hardy,O
-,O
Weinberg,O
equilibrium,O
.,O
 , 
However,O
,,O
the,O
frequency,O
of,O
one,O
allele,O
and,O
one,O
genotype,O
was,O
significantly,O
different,O
between,O
males,O
and,O
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
and,O
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
,,O
and,O
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
cohort,O
of,O
PEX1,B-Gene
-,I-Gene
deficient,O
PBD,O
patients,O
.,O
 , 
This,O
screen,O
has,O
identified,O
five,O
novel,O
mutations,O
,,O
including,O
nonsense,O
mutations,O
in,O
exons,O
14,O
and,O
19,O
and,O
single,O
nucleotide,O
deletions,O
in,O
exons,O
5,O
and,O
18,O
.,O
 , 
Significantly,O
,,O
the,O
allele,O
carrying,O
the,O
exon,O
18,O
frameshift,O
mutation,O
is,O
present,O
at,O
moderately,O
high,O
frequency,O
(,O
approx,O
.,O
 , 
10,O
%,O
),O
in,O
this,O
patient,O
cohort,O
.,O
 , 
The,O
fifth,O
mutation,O
is,O
a,O
missense,O
mutation,O
(,B-SNP
R798,I-SNP
G,I-SNP
),I-SNP
that,O
attenuates,O
,,O
but,O
does,O
not,O
abolish,O
PEX1,B-Gene
function,O
.,O
 , 
We,O
have,O
evaluated,O
the,O
cellular,O
impact,O
of,O
these,O
novel,O
mutations,O
,,O
along,O
with,O
that,O
of,O
the,O
two,O
most,O
common,O
PEX1,B-Gene
mutations,O
(,B-SNP
c.2097,I-SNP
-,I-SNP
2098insT,I-SNP
and,O
G843D,B-SNP
),I-SNP
,,O
in,O
PBD,O
patients,O
by,O
determining,O
the,O
levels,O
of,O
PEX1,O
mRNA,O
,,O
PEX1,B-Gene
protein,O
,,O
and,O
peroxisome,O
protein,O
import,O
.,O
 , 
The,O
findings,O
are,O
consistent,O
with,O
a,O
close,O
correlation,O
between,O
cellular,O
phenotype,O
,,O
disease,O
severity,O
,,O
and,O
PEX1,O
genotype,O
.,O
 , 
#15739154
Molecular,O
and,O
clinical,O
analyses,O
of,O
Greig,O
cephalopolysyndactyly,O
and,O
Pallister,O
-,O
Hall,O
syndromes,O
:,O
robust,O
phenotype,O
prediction,O
from,O
the,O
type,O
and,O
position,O
of,O
GLI3,B-Gene
mutations,O
.,O
 , 
Mutations,O
in,O
the,O
GLI3,B-Gene
zinc,B-Gene
-,I-Gene
finger,I-Gene
transcription,I-Gene
factor,I-Gene
gene,O
cause,O
Greig,O
cephalopolysyndactyly,O
syndrome,O
(,O
GCPS,O
),O
and,O
Pallister,O
-,O
Hall,O
syndrome,O
(,O
PHS,O
),O
,,O
which,O
are,O
variable,O
but,O
distinct,O
clinical,O
entities,O
.,O
 , 
We,O
hypothesized,O
that,O
GLI3,B-Gene
mutations,O
that,O
predict,O
a,O
truncated,O
functional,O
repressor,O
protein,O
cause,O
PHS,O
and,O
that,O
functional,O
haploinsufficiency,O
of,O
GLI3,B-Gene
causes,O
GCPS,O
.,O
 , 
To,O
test,O
these,O
hypotheses,O
,,O
we,O
screened,O
patients,O
with,O
PHS,O
and,O
GCPS,O
for,O
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
;,O
when,O
these,O
were,O
combined,O
with,O
previously,O
published,O
mutations,O
,,O
two,O
genotype,O
-,O
phenotype,O
correlations,O
were,O
evident,O
.,O
 , 
First,O
,,O
GCPS,O
was,O
caused,O
by,O
many,O
types,O
of,O
alterations,O
,,O
including,O
translocations,O
,,O
large,O
deletions,O
,,O
exonic,O
deletions,O
and,O
duplications,O
,,O
small,O
in,O
-,O
frame,O
deletions,O
,,O
and,O
missense,O
,,O
frameshift,O
/,O
nonsense,O
,,O
and,O
splicing,O
mutations,O
.,O
 , 
In,O
contrast,O
,,O
PHS,O
was,O
caused,O
only,O
by,O
frameshift,O
/,O
nonsense,O
and,O
splicing,O
mutations,O
.,O
 , 
Second,O
,,O
among,O
the,O
frameshift,O
/,O
nonsense,O
mutations,O
,,O
there,O
was,O
a,O
clear,O
genotype,O
-,O
phenotype,O
correlation,O
.,O
 , 
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
ORF,O
],O
nucleotides,O
[,O
nt,O
],O
1,O
-,O
1997,O
),O
caused,O
GCPS,O
,,O
and,O
mutations,O
in,O
the,O
second,O
third,O
of,O
the,O
gene,O
(,O
from,O
ORF,O
nt,O
1998,O
-,O
3481,O
),O
caused,O
primarily,O
PHS,O
.,O
 , 
Surprisingly,O
,,O
there,O
were,O
12,O
mutations,O
in,O
patients,O
with,O
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
demonstrate,O
a,O
robust,O
correlation,O
of,O
genotype,O
and,O
phenotype,O
for,O
GLI3,B-Gene
mutations,O
and,O
strongly,O
support,O
the,O
hypothesis,O
that,O
these,O
two,O
allelic,O
disorders,O
have,O
distinct,O
modes,O
of,O
pathogenesis,O
.,O
 , 
#7942859
The,O
power,O
of,O
interval,O
mapping,O
of,O
quantitative,O
trait,O
loci,O
,,O
using,O
selected,O
sib,O
pairs,O
.,O
 , 
The,O
interval,O
-,O
mapping,O
procedure,O
of,O
Fulker,O
and,O
Cardon,O
for,O
analysis,O
of,O
a,O
quantitative,O
-,O
trait,O
loci,O
(,O
QTL,O
),O
is,O
extended,O
for,O
application,O
to,O
selected,O
samples,O
of,O
sib,O
pairs,O
.,O
 , 
Phenotypic,O
selection,O
of,O
sib,O
pairs,O
,,O
which,O
is,O
known,O
to,O
yield,O
striking,O
increases,O
in,O
power,O
when,O
a,O
single,O
marker,O
is,O
used,O
,,O
provides,O
further,O
increases,O
in,O
power,O
when,O
the,O
interval,O
-,O
mapping,O
approach,O
is,O
used,O
.,O
 , 
The,O
greatest,O
benefits,O
of,O
the,O
combined,O
approach,O
are,O
apparent,O
with,O
coarse,O
maps,O
,,O
where,O
QTLs,O
of,O
relatively,O
modest,O
(,O
15%-20,O
%,O
),O
heritability,O
can,O
be,O
detected,O
with,O
widely,O
spaced,O
markers,O
(,O
40,O
-,O
60,O
cM,O
apart,O
),O
in,O
reasonably,O
sized,O
sibling,O
samples,O
.,O
 , 
Useful,O
information,O
concerning,O
QTL,O
location,O
is,O
afforded,O
by,O
interval,O
mapping,O
in,O
both,O
selected,O
and,O
unselected,O
samples,O
.,O
 , 
#17701907
Evidence,O
of,O
still,O
-,O
ongoing,O
convergence,O
evolution,O
of,O
the,O
lactase,O
persistence,O
T-13910,O
alleles,O
in,O
humans,O
.,O
 , 
A,O
single,O
-,O
nucleotide,O
variant,O
,,O
C,B-SNP
/,I-SNP
T(-13910,I-SNP
),I-SNP
,,I-SNP
located,O
14,O
kb,O
upstream,O
of,O
the,O
lactase,B-Gene
gene,O
(,B-Gene
LCT,I-Gene
),I-Gene
,,O
has,O
been,O
shown,O
to,O
be,O
completely,O
correlated,O
with,O
lactase,O
persistence,O
(,O
LP,O
),O
in,O
northern,O
Europeans,O
.,O
 , 
Here,O
,,O
we,O
analyzed,O
the,O
background,O
of,O
the,O
alleles,O
carrying,O
the,O
critical,O
variant,O
in,O
1,611,O
DNA,O
samples,O
from,O
37,O
populations,O
.,O
 , 
Our,O
data,O
show,O
that,O
the,O
T(-13910,O
),O
variant,O
is,O
found,O
on,O
two,O
different,O
,,O
highly,O
divergent,O
haplotype,O
backgrounds,O
in,O
the,O
global,O
populations,O
.,O
 , 
The,O
first,O
is,O
the,O
most,O
common,O
LP,O
haplotype,O
(,O
LP,O
H98,O
),O
present,O
in,O
all,O
populations,O
analyzed,O
,,O
whereas,O
the,O
others,O
(,O
LP,O
H8,O
-,O
H12,O
),O
,,O
which,O
originate,O
from,O
the,O
same,O
ancestral,O
allelic,O
haplotype,O
,,O
are,O
found,O
in,O
geographically,O
restricted,O
populations,O
living,O
west,O
of,O
the,O
Urals,O
and,O
north,O
of,O
the,O
Caucasus,O
.,O
 , 
The,O
global,O
distribution,O
pattern,O
of,O
LP,O
T(-13910,O
),O
H98,O
supports,O
the,O
Caucasian,O
origin,O
of,O
this,O
allele,O
.,O
 , 
Age,O
estimates,O
based,O
on,O
different,O
mathematical,O
models,O
show,O
that,O
the,O
common,O
LP,O
T(-13910,O
),O
H98,O
allele,O
(,O
approximately,O
5,000,O
-,O
12,000,O
years,O
old,O
),O
is,O
relatively,O
older,O
than,O
the,O
other,O
geographically,O
restricted,O
LP,O
alleles,O
(,O
approximately,O
1,400,O
-,O
3,000,O
years,O
old,O
),O
.,O
 , 
Our,O
data,O
about,O
global,O
allelic,O
haplotypes,O
of,O
the,O
lactose,O
-,O
tolerance,O
variant,O
imply,O
that,O
the,O
T(-13910,O
),O
allele,O
has,O
been,O
independently,O
introduced,O
more,O
than,O
once,O
and,O
that,O
there,O
is,O
a,O
still,O
-,O
ongoing,O
process,O
of,O
convergent,O
evolution,O
of,O
the,O
LP,O
alleles,O
in,O
humans,O
.,O
 ,