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A robust statistical method for case-control association testing with copy number variation.: Nature genetics (7 September 2008)Copy number variation (CNV) is pervasive in the human genome and can play a causal role in genetic diseases. The functional impact of CNV cannot be fully captured through linkage disequilibrium with SNPs. These observations motivate the development of statistical methods for performing direct CNV association studies. We show through simulation that current tests for CNV association are prone to false-positive associations in the presence of differential errors between cases and controls, especially if quantitative CNV measurements are noisy. We present a statistical framework for performing case-control CNV association studies that applies likelihood ratio testing of quantitative CNV measurements in cases and controls. We show that our methods are robust to differential errors and noisy data and can achieve maximal theoretical power. We illustrate the power of these methods for testing for association with binary and quantitative traits, and have made this software available as the R package CNVtools.Chris Barnes, Vincent Plagnol, Tomas Fitzgerald, Richard Redon, Jonathan Marchini, David Clayton, Matthew E Hurles

Source: Nature genetics (7 September 2008)
A high-resolutio n survey of deletion polymorphism in the human genome: Nature Genetics, Vol. 38, No. 1. (04 December 2005), pp. 75-81.Donald Conrad, Daniel Andrews, Nigel Carter, Matthew Hurles, Jonathan Pritchard

Source: Nature Genetics, Vol. 38, No. 1. (04 December 2005), pp. 75-81.
Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome.: Am J Hum Genet, Vol. 79, No. 2. (August 2006), pp. 275-290.Studie s of copy-number variation and linkage disequilibrium (LD) have typically excluded complex regions of the genome that are rich in duplications and prone to rearrangement. In an attempt to assess the heritability and LD of copy-number polymorphisms (CNPs) in duplication-ri ch regions of the genome, we profiled copy-number variation in 130 putative "rearrangement hotspot regions" among 269 individuals of European, Yoruba, Chinese, and Japanese ancestry analyzed by the International HapMap Consortium. Eighty-four hotspot regions, corresponding to 257 bacterial artificial chromosome (BAC) probes, showed evidence of copy-number differences. Despite a predisposing genetic architecture, no polymorphism was ever observed in the remaining 46 "rearrangement hotspots," and we suggest these represent excellent candidate sites for pathogenic rearrangements . We used a combination of BAC-based and high-density customized oligonucleotid e arrays to resolve the molecular basis of structural rearrangements . For common variants (frequency >10%), we observed a distinct bias against copy-number losses, suggesting that deletions are subject to purifying selection. Heritability estimates did not differ significantly from 1.0 among the majority (30 of 34) of loci analyzed, consistent with normal Mendelian inheritance. Some of the CNPs in duplication-ri ch regions showed strong LD with nearby single-nucleot ide polymorphisms (SNPs) and were observed to segregate on ancestral SNP haplotypes. However, LD with the best available SNP markers was weaker than has been reported for deletion polymorphisms in less complex regions of the genome. These observations may be accounted for by a low density of SNP data in duplicated regions, challenges in mapping and typing the CNPs, and the possibility that CNPs in these regions have rearranged on multiple haplotype backgrounds. Our results underscore the need for complete maps of genetic variation in duplication-ri ch regions of the genome.DP Locke, AJ Sharp, SA McCarroll, SD McGrath, TL Newman, Z Cheng, S Schwartz, DG Albertson, D Pinkel, DM Altshuler, EE Eichler

Source: Am J Hum Genet, Vol. 79, No. 2. (August 2006), pp. 275-290.
Mutational and selective effects on copy-number variants in the human genome.: Nat Genet, Vol. 39, No. 7 Suppl. (July 2007)Comprehen sive descriptions of large insertion/dele tion or segmental duplication polymorphisms (SDs) in the human genome have recently been generated. These annotations, known collectively as structural or copy-number variants (CNVs), include thousands of discrete genomic regions and span hundreds of millions of nucleotides. Here we review the genomic distribution of CNVs, which is strongly correlated with gene, repeat and segmental duplication content. We explore the evolutionary mechanisms giving rise to this nonrandom distribution, considering the available data on both human polymorphisms and the fixed changes that differentiate humans from other species. It is likely that mutational biases, selective effects and interactions between these forces all contribute substantially to the spectrum of human copy-number variation. Although defining these variants with nucleotide-lev el precision remains a largely unmet but critical challenge, our understanding of their potential medical impact and evolutionary importance is rapidly emerging.GM Cooper, DA Nickerson, EE Eichler

Source: Nat Genet, Vol. 39, No. 7 Suppl. (July 2007)
Allele Frequency Matching Between SNPs Reveals an Excess of Linkage Disequilibrium in Genic Regions of the Human Genome: PLoS Genetics, Vol. 2, No. 9. (1 September 2006), e142.Significa nt interest has emerged in mapping genetic susceptibility for complex traits through whole-genome association studies. These studies rely on the extent of association, i.e., linkage disequilibrium (LD), between single nucleotide polymorphisms (SNPs) across the human genome. LD describes the nonrandom association between SNP pairs and can be used as a metric when designing maximally informative panels of SNPs for association studies in human populations. Using data from the 1.58 million SNPs genotyped by Perlegen, we explored the allele frequency dependence of the LD statistic r2 both empirically and theoretically. We show that average r2 values between SNPs unmatched for allele frequency are always limited to much less than 1 (theoretical approximately 0.46 to 0.57 for this dataset). Frequency matching of SNP pairs provides a more sensitive measure for assessing the average decay of LD and generates average r2 values across nearly the entire informative range (from 0 to 0.89 through 0.95). Additionally, we analyzed the extent of perfect LD (r2 = 1.0) using frequency-matc hed SNPs and found significant differences in the extent of LD in genic regions versus intergenic regions. The SNP pairs exhibiting perfect LD showed a significant bias for derived, nonancestral alleles, providing evidence for positive natural selection in the human genome.Michael Eberle, Mark Rieder, Leonid Kruglyak, Deborah Nickerson

Source: PLoS Genetics, Vol. 2, No. 9. (1 September 2006), e142.
Possible Ancestral Structure in Human Populations: PLoS Genetics, Vol. 2, No. 7. (1 July 2006), e105.Determini ng the evolutionary relationships between fossil hominid groups such as Neanderthals and modern humans has been a question of enduring interest in human evolutionary genetics. Here we present a new method for addressing whether archaic human groups contributed to the modern gene pool (called ancient admixture), using the patterns of variation in contemporary human populations. Our method improves on previous work by explicitly accounting for recent population history before performing the analyses. Using sequence data from the Environmental Genome Project, we find strong evidence for ancient admixture in both a European and a West African population (p ? 10?7), with contributions to the modern gene pool of at least 5%. While Neanderthals form an obvious archaic source population candidate in Europe, there is not yet a clear source population candidate in West Africa.Vincent Plagnol, Jeffrey Wall

Source: PLoS Genetics, Vol. 2, No. 7. (1 July 2006), e105.
Linkage Disequilibrium in Humans: Models and Data: The American Journal of Human Genetics, Vol. 69, No. 1. (July 2001), pp. 1-14.In this review, we describe recent empirical and theoretical work on the extent of linkage disequilibrium (LD) in the human genome, comparing the predictions of simple population-gen etic models to available data. Several studies report significant LD over distances longer than those predicted by standard models, whereas some data from short, intergenic regions show less LD than would be expected. The apparent discrepancies between theory and data present a challenge--bot h to modelers and to human geneticists--t o identify which important features are missing from our understanding of the biological processes that give rise to LD. Salient features may include demographic complications such as recent admixture, as well as genetic factors such as local variation in recombination rates, gene conversion, and the potential segregation of inversions. We also outline some implications that the emerging patterns of LD have for association-ma pping strategies. In particular, we discuss what marker densities might be necessary for genomewide association scans.Jonathan Pritchard, Molly Przeworski

Source: The American Journal of Human Genetics, Vol. 69, No. 1. (July 2001), pp. 1-14.
A high-resolutio n recombination map of the human genome.: Nat Genet, Vol. 31, No. 3. (July 2002), pp. 241-247.Determ ination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolutio n genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T ) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.A Kong, DF Gudbjartsson, J Sainz, GM Jonsdottir, SA Gudjonsson, B Richardsson, S Sigurdardottir , J Barnard, B Hallbeck, G Masson, A Shlien, ST Palsson, ML Frigge, TE Thorgeirsson, JR Gulcher, K Stefansson

Source: Nat Genet, Vol. 31, No. 3. (July 2002), pp. 241-247.
Two-Locus Sampling Distributions and Their Application: Genetics, Vol. 159, No. 4. (1 December 2001), pp. 1805-1817.Meth ods of estimating two-locus sample probabilities under a neutral model are extended in several ways. Estimation of sample probabilities is described when the ancestral or derived status of each allele is specified. In addition, probabilities for two-locus diploid samples are provided. A method for using these two-locus probabilities to test whether an observed level of linkage disequilibrium is unusually large or small is described. In addition, properties of a maximum-likeli hood estimator of the recombination parameter based on independent linked pairs of sites are obtained. A composite-like lihood estimator, for more than two linked sites, is also examined and found to work as well, or better, than other available ad hoc estimators. Linkage disequilibrium in the Xq28 and Xq25 region of humans is analyzed in a sample of Europeans (CEPH). The estimated recombination parameter is about five times smaller than one would expect under an equilibrium neutral model.Richard Hudson

Source: Genetics, Vol. 159, No. 4. (1 December 2001), pp. 1805-1817.
The Interaction of Selection and Linkage. I. General Considerations ; Heterotic Models.: Genetics, Vol. 49, No. 1. (January 1964), pp. 49-67.RC Lewontin

Source: Genetics, Vol. 49, No. 1. (January 1964), pp. 49-67.

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