Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome
Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome
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DOI：
10.1086/505653
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发表时间：
2006-08-01
影响因子：
9.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Locke, Devin P.;Sharp, Andrew J.;Eichler, Evan E.
拷贝数变异和连锁不平衡 (LD) 的研究通常排除基因组中富含重复且易于重排的复杂区域。为了评估基因组重复丰富区域中拷贝数多态性 (CNP) 的遗传力和 LD，我们对国际单体型图联盟 (International HapMap Consortium) 分析的欧洲、约鲁巴、中国和日本血统的 269 个个体中 130 个假定的“重排热点区域”的拷贝数变异进行了分析。 84 个热点区域，对应 257 个细菌人工染色体 (BAC) 探针，显示出拷贝数差异的证据。尽管存在易感遗传结构，但在其余 46 个“重排热点”中未观察到多态性，我们认为这些代表了致病性重排的极好候选位点。我们结合使用基于 BAC 和高密度定制寡核苷酸阵列来解析结构重排的分子基础。对于常见变异（频率 > 10%），我们观察到对拷贝数丢失的明显偏差，这表明删除受到纯化选择的影响。在大多数（34 个）分析基因座中，遗传力估计值与 1.0 没有显着差异，与正常孟德尔遗传一致。重复丰富区域中的一些 CNP 显示出具有附近单核苷酸多态性 (SNP) 的强 LD，并且观察到在祖先 SNP 单倍型上发生分离。然而，具有最佳可用 SNP 标记的 LD 比已报道的基因组不太复杂区域中的缺失多态性弱。这些观察结果可能是由于重复区域中的 SNP 数据密度低、CNP 定位和分型方面的挑战以及这些区域中的 CNP 在多个单倍型背景下重新排列的可能性造成的。我们的结果强调了对基因组重复丰富区域的遗传变异的完整图谱的需求。
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.