TY - JOUR
T1 - Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome
AU - Locke, Devin P.
AU - Sharp, Andrew J.
AU - McCarroll, Steven A.
AU - McGrath, Sean D.
AU - Newman, Tera L.
AU - Cheng, Ze
AU - Schwartz, Stuart
AU - Albertson, Donna G.
AU - Pinkel, Daniel
AU - Altshuler, David M.
AU - Eichler, Evan E.
N1 - Funding Information:
S.A.M. contributed equally with D.P.L. and A.J.S. to this manuscript but, because of journal policy, could not be listed as a joint primary author. We thank Joshua Akey for critical comments in the preparation of this manuscript. This work was supported in part by National Institutes of Health (NIH) grant HD043569 and supplemental funds from NIH grant HG002385 (to E.E.E.) and by a fellowship from Merck Research Laboratories (to A.J.S.). Somatic tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute. E.E.E. is an Investigator of the Howard Hughes Medical Institute.
PY - 2006/8
Y1 - 2006/8
N2 - 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 duplicationrich 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.
AB - 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 duplicationrich 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.
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U2 - 10.1086/505653
DO - 10.1086/505653
M3 - Article
C2 - 16826518
AN - SCOPUS:33746513094
SN - 0002-9297
VL - 79
SP - 275
EP - 290
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -