Human copy number polymorphic genes

Abstract

Recent large-scale genomic studies within human populations have identified numerous genomic regions as copy number variant (CNV). As these CNV regions often overlap coding regions of the genome, large lists of potentially copy number polymorphic genes have been produced that are candidates for disease association. Most of the current data regarding normal genic variation, however, has been generated using BAC or SNP microarrays, which lack precision especially with respect to exons. To address this, we assessed 2,790 candidate CNV genes defined from available studies in nine well-characterized HapMap individuals by designing a customized oligonucleotide microarray targeted specifically to exons. Using exon array comparative genomic hybridization (aCGH), we detected 255 (9%) of the candidates as true CNVs including 134 with evidence of variation over the entire gene. Individuals differed in copy number from the control by an average of 100 gene loci. Both partial- and whole-gene CNVs were strongly associated with segmental duplications (55 and 71%, respectively) as well as regions of positive selection. We confirmed 37% of the whole-gene CNVs using the fosmid end sequence pair (ESP) structural variation map for these same individuals. If we modify the end sequence pair mapping strategy to include low-sequence identity ESPs (98–99.5%) and ESPs with an everted orientation, we can capture 82% of the missed genes leading to more complete ascertainment of structural variation within duplicated genes. Our results indicate that segmental duplications are the source of the majority of full-length copy number polymorphic genes, most of the variant genes are organized as tandem duplications, and a significant fraction of these genes will represent paralogs with levels of sequence diversity beyond thresholds of allelic variation. In addition, these data provide a targeted set of CNV genes enriched for regions likely to be associated with human phenotypic differences due to copy number changes and present a source of copy number responsive oligonucleotide probes for future association studies.

A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

“…We controlled for population stratification, applied filters which are stringent for CNV studies, and utilized 2 different CNV calling algorithms to ensure comprehensive detection of CNVs. Some of the reported CNV regions in this study were indeed characterized as disease conferring across a spectrum of phenotypes and therefore provide confidence in our study findings [Butler et al, 2005;Bailey et al, 2008;Diskin et al, 2009;Glessner et al, 2009Glessner et al, , 2010Ehli et al, 2012;Stadler et al, 2012;Lalani et al, 2013;Nagamani et al, 2013;Ukkola-Vuoti et al, 2013;Chettier et al, 2014;Szatkiewicz et al, 2014;Furuya et al, 2015].…”

“…In addition to SNPs as heritable markers, variations in the germline DNA such as insertions, deletions, and copy number variations (CNVs) are hypothesized to confer genetic susceptibility to complex traits [Feuk et al, 2006;Conrad and Hurles, 2007;McCarroll and Altshuler, 2007;Bailey et al, 2008;Diskin et al, 2009;Conrad et al, 2010b;McCarroll, 2010;Wellcome Trust Case Control Consortium et al, 2010;Masson et al, 2014;Handsaker et al, 2015]. Germline CNVs, therefore, are pursued as potential candidates to explain the missing heritability.…”

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

“…32,33 However, there have been few studies assessing a large set of candidate genes thought to be causative for a complex and highly heterogeneous condition like ID. 34 Therefore, the aim of our study was to design a custom array able to identify CNVs in known ID genes/loci as well as in candidate ID genes, at single-exon resolution, which is well below the current level of detection of standard clinical CMA.…”

The Evolution of Human Segmental Duplications and the Core Duplicon Hypothesis

“…Not surprisingly, SDs are significantly enriched for copy-number polymorphisms (Iafrate et al 2004; Sharp et al 2005; Redon et al 2006) with most of the genic copy-number polymorphisms mapping to these regions of the genome (Cooper et al 2007; Bailey et al 2008). The fact that so many of these duplications are interspersed, however, is double jeopardy for humans and its most closely related ape species.…”