Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENETICS IN DEVELOPMENTAL DISORDERS <s> The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult. In their Perspective, Risch and Merikangas propose that we can best accomplish this goal by combining the power of the human genome project with association studies, a method for determining the basis of a genetic disease. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENETICS IN DEVELOPMENTAL DISORDERS <s> What will happen after a complete sequence of the human genome is available? Eric Lander argues that it will be the beginning of a new phase of research. He presents 10 goals for the future that are related to a global view of biology. The author is at the Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENETICS IN DEVELOPMENTAL DISORDERS <s> Human disease genes show enormous variation in their allelic spectra; that is, in the number and population frequency of the disease-predisposing alleles at the loci. For some genes, there are a few predominant disease alleles. For others, there is a wide range of disease alleles, each relatively rare. The allelic spectrum is important: disease genes with only a few deleterious alleles can be more readily identified and are more amenable to clinical testing. Here, we weave together strands from the human mutation and population genetics literature to provide a framework for understanding and predicting the allelic spectra of disease genes. The theory does a reasonable job for diseases where the genetic etiology is well understood. It also has bearing on the Common Disease/Common Variants (CD/CV) hypothesis, predicting that at loci where the total frequency of disease alleles is not too small, disease loci will have relatively simple spectra. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENETICS IN DEVELOPMENTAL DISORDERS <s> We report the identification and characterization of 2,000 human diallelic insertion/deletion polymorphisms (indels) distributed throughout the human genome. Candidate indels were identified by comparison of overlapping genomic or cDNA sequences. Average confirmation rate for indels with a ⩾2-nt allele-length difference was 58%, but the confirmation rate for indels with a 1-nt length difference was only 14%. The vast majority of the human diallelic indels were monomorphic in chimpanzees and gorillas. The ratio of deletion:insertion mutations was 4.1. Allele frequencies for the indels were measured in Europeans, Africans, Japanese, and Native Americans. New alleles were generally lower in frequency than old alleles. This tendency was most pronounced for the Africans, who are likely to be closest among the four groups to the original modern human population. Diallelic indels comprise ∼8% of all human polymorphisms. Their abundance and ease of analysis make them useful for many applications. <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENETICS IN DEVELOPMENTAL DISORDERS <s> There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The 'Common Disease, Common Variant (CDCV)' hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low 'penetrance' (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common diseases. The 'Common Disease, Rare Variant (CDRV)' hypothesis, on the contrary, argues that multiple rare DNA sequence variations, each with relatively high penetrance, are the major contributors to genetic susceptibility to common diseases. Both hypotheses have their place in current research efforts. <s> BIB005
The field of genetics took hold as a modern science following Mendel's foundational work in the mid-late 1800s and was furthered by a number of remarkable discoveries throughout the 20th century that led to the discovery of the genetic basis for many diseases. Following early genetic sequencing efforts in the 1970s and 1980s, the successful sequencing of the human genome was accomplished in 2003 (Human Genome Sequencing Consortium, 2004) . This sequencing did not uncover a deterministic map of human traits and diseases but instead revealed a basic architecture from which complex interactions among genes, behavior, and environment dictate human ontogenesis  . Uncovering this architecture has paved the way for advances in analytic approaches for exploring the nature of gene-behavior relations. Previously, the primary method for uncovering the genetic underpinnings of particular traits was through linkage analysis. This technique allowed researchers to use genetic markers to identify the locations of the segment(s) of DNA in chromosomes that are shared by individuals within a family who exhibit a trait of interest  . Linkage analysis is a useful tool for establishing inheritance in single-gene Mendelian disorders because it is based on deviations from expected patterns of inheritance and it traces cotransmission of a DNA marker allele and a disorder. For single-gene disorders, linkage can be identified by using  Skeide et al. a few large family pedigrees; for the study of complex traits, the affected sib-pair linkage design which examines allele sharing for pairs of affected siblings in many different families is the most widely used linkage design  . However, linkage approaches require a large gene effect for successful detection and thus have limited power for identification of genes of modest effect that contribute to complex traits and disorders BIB001 . The vast majority of complex traits, conditions, and behaviors arise from the presence of multiple genetic variations or polymorphisms as well as gene-by-gene and gene-byenvironment interactions. These include both common variants, which are present in greater than 1% of the genome, and rare variants, which occur in less than 1% of the genome. The most frequently occurring polymorphisms are single nucleotide polymorphisms (SNPs), in which there is a single base pair substitution in the structural units of DNA (The International SNP Map Working Group, 2001)-these represent approximately 90% of the variation in human DNA (The 1000 Genomes Project Consortium, 2011). Additional variation comes from insertion-deletion polymorphisms (indels) which affect one or more base pairs by the removal or addition of units BIB004 and copy number variations (CNVs) which represent alterations in the position or number of copies of larger sequences of DNA  . SNPs and other common variants are of great scientific interest as markers of risk for genetic diseases or conditions in the general population because they occur relatively frequently and modest gene effects can be detected using association studies that do not require large family pedigrees. Researchers who seek to understand the genetic origins of common diseases and traits are guided by two predominant hypotheses: the common disease/common variant (CDCV) hypothesis and the common disease/rare variant hypothesis (CDRV). According to CDCV, variants that are common in the population but have low penetrance (i.e., the probability that the carrier of the variant will express the disease) play a primary role in disease susceptibility BIB002 BIB003 BIB005 . In contrast, CDRV suggests that rare variants with high penetrance are the major contributors to disease susceptibility BIB005 . Evidence supports both of these models BIB005 , and while ongoing research continues to contrast these models, a hybrid account for complex disease and trait susceptibility holds the most explanatory power. Consistent with the CDCV hypothesis, many of the identified genetic variants associated with SRD and DLD are (a) fairly common in the general population 2 ; (b) carried by only a small subset of individuals with these disorders; and (c) not clearly linked to the behavioral phenotype of the individuals who carry them. There are, however, some rare variants associated with language and reading phenotypes which have been found in more severely impaired individuals,