Linkage Disequilibrium and Heritability of Copy-Number Polymorphisms within Duplicated Regions of the Human Genome

Abstract

Studies 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-rich 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 oligonucleotide 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-rich regions showed strong LD with nearby single-nucleotide 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-rich regions of the genome.

On a novel coalescent model for genome-wide evolution of Copy Number Variations

“…This region is located near the region of SD as reported in Locke et al (2006). Even more interestingly, this region shows the same heterogeneous patterns in all four populations, suggesting that this polymorphism may be ancient and may have suffered multiple modifications.…”

“…Regions of SD in the genome have been known as regions prone to chromosomal instability, recombination and recurrent chromosomal rearrangements associated with certain genomic diseases. These regions have attracted interest of many scientists as their connections to CNVs have become apparent; see the discussions in Sharp et al (2005), Locke et al (2006) and Redon et al (2006). For instance, Sharp et al (2005) and Locke et al (2006), noticed a significant enrichment of CNVs in the neighbourhood of recombination hot-spots, as compared to any arbitrary control region in the genome.…”

“…These regions have attracted interest of many scientists as their connections to CNVs have become apparent; see the discussions in Sharp et al (2005), Locke et al (2006) and Redon et al (2006). For instance, Sharp et al (2005) and Locke et al (2006), noticed a significant enrichment of CNVs in the neighbourhood of recombination hot-spots, as compared to any arbitrary control region in the genome. The authors thus concluded that SDs might be major mediators of large-scale variation in the human genome.…”

“…To distinguish CNVs from normal copy values we have used a criterion similar to the one used by Sharp et al (2005) and Locke et al (2006). In particular, to account for asymmetry in some hybridisation data, we used the following statistical method to identify variants in an asymmetric distribution.…”

“…For example, many studies have observed the enrichment of CNVs in the regions of segmental duplications; see Sharp et al (2005) and Locke et al (2006). Additionally, Redon et al (2006) noticed that various CNVs, specifically multi-allelic, complex and combined deletion-amplification CNVs, are markedly enriched for Segmental Duplications (SDs).…”