Patterns of genetic variation in Mendelian and complex traits

Department of Genetics, and Center for Human Genetics, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Annual Review of Genomics and Human Genetics (Impact Factor: 8.96). 02/2000; 1(2000):387-407. DOI: 10.1146/annurev.genom.1.1.387
Source: PubMed


This review discusses the prospects for understanding the genetic basis of complex traits in humans. We take the view that work done on Drosophila melanogaster can serve as a model for understanding complex traits in humans, and the literature on this model system, as well as on humans, is reviewed. The prospects for success in understanding the genetic basis of complex traits depend, in part, on the nature of the forces acting on genetic variation. We suggest that different experimental approaches should be undertaken for traits caused by common genetic variants versus those arising from rare genetic variants.

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    • "Such studies have been done for both rare ( " Mendelian " ) and common (mostly " complex " ) diseases. The dividing line between Mendelian and complex diseases may be considered vague and simplistic, but Mendelian diseases are usually rare and mostly result from highly penetrant, deleterious alleles that segregate in families (Zwick et al. 2000; Pritchard and Cox 2002). However, most phenotypic differences in morphology, physiology , and disease are quantitative rather than discrete and follow a continuous, almost normal distribution (Pritchard and Cox 2002). "
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    ABSTRACT: Progress in genomic technologies, such as DNA arrays and next-generation sequencing, is allowing systematic characterization of the degree of human genetic variation at the scale of individual genomes. Public efforts, such as the International HapMap Project and the 1000 Genomes Project, have provided a realistic picture of the levels of genetic diversity in individuals and populations. These genomic techniques are also making it possible to evaluate the contribution of host genetic diversity to differences in susceptibility to both rare and common infectious diseases. Recent studies have revealed the power of whole-exome sequencing for dissecting the immunological mechanisms underlying the pathogenesis of severe, rare infectious diseases. Likewise, genome-wide association studies on common viral, bacterial, and parasitic infections have shed light on the host genetic basis of susceptibility to infectious diseases and, in some cases, of disease progression and drug responses.
    Cold Spring Harbor Perspectives in Medicine 01/2013; 3(1). DOI:10.1101/cshperspect.a012450 · 9.47 Impact Factor
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    • "For the past 15 years, genomic studies of complex diseases have relied on a model in which common genetic variation contributes significantly to common diseases [82-84]. Based on this model, the systematic genotyping of common variants was perceived as the best way to begin characterizing the allelic architecture of complex human traits [85]. To make such experiments possible required the development of highly accurate, low-cost, high-throughput genotyping platforms and a catalog of common human genetic variation like the HapMap project [86,87]. "
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    ABSTRACT: Background Autism spectrum disorder (ASD) is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. Methods We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. Results We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3’ UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. Conclusions These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects.
    Molecular Autism 09/2012; 3(1):8. DOI:10.1186/2040-2392-3-8 · 5.41 Impact Factor
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    • "While SNPs are certainly an important source of variation between human genomes, there are a few reasons why DNPs and TNPs have a greater propensity to be involved in disease causing mutations. First, SNPs have a strong propensity to be synonymous (13) whereby they change the nucleotide sequence, but do not alter the amino acid sequence due to the wobble allowed by the genetic code. These synonymous changes are usually silent and do not effect the phenotype, but there are notable exceptions (14,15). "
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    ABSTRACT: Genomic sequence comparisons between individuals are usually restricted to the analysis of single nucleotide polymorphisms (SNPs). While the interrogation of SNPs is efficient, they are not the only form of divergence between genomes. In this report, we expand the scope of polymorphism detection by investigating the occurrence of double nucleotide polymorphisms (DNPs) and triple nucleotide polymorphisms (TNPs), in which two or three consecutive nucleotides are altered compared to the reference sequence. We have found such DNPs and TNPs throughout two complete genomes and eight exomes. Within exons, these novel polymorphisms are over-represented amongst protein-altering variants; nearly all DNPs and TNPs result in a change in amino acid sequence and, in some cases, two adjacent amino acids are changed. DNPs and TNPs represent a potentially important new source of genetic variation which may underlie human disease and they should be included in future medical genetics studies. As a confirmation of the damaging nature of xNPs, we have identified changes in the exome of a glioblastoma cell line that are important in glioblastoma pathogenesis. We have found a TNP causing a single amino acid change in LAMC2 and a TNP causing a truncation of HUWE1.
    Nucleic Acids Research 10/2010; 38(18):6102-11. DOI:10.1093/nar/gkq408 · 9.11 Impact Factor
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