Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.
Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.
复制标题
纯合性运行中有害纯合子的祖先依赖性富集。
DOI：
10.1016/j.ajhg.2019.08.011
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发表时间：
2019
影响因子：
9.8
通讯作者：
Hernandez,RyanD
中科院分区：
文献类型：
--
作者：
Szpiech,ZacharyA;Mak,AngelCY;White,MarquittaJ;Hu,Donglei;Eng,Celeste;Burchard,EstebanG;Hernandez,RyanD
纯合性运行 (ROH) 是重要的基因组特征，当个体继承两个血统相同的单倍型时就会显现出来。它们的长度分布可以提供有关种群历史的信息，它们的基因组位置可用于绘制导致孟德尔疾病风险和复杂疾病风险的隐性基因座。我们之前已经表明，ROH，特别是长ROH，可能是最近亲本相关性的结果，在全球远交个体样本中富含纯合有害编码变异。然而，ROH 在混合群体中的分布及其与有害纯合基因型的关系尚未得到充分研究。在这里，我们分析了 1,441 名无关个体的全基因组测序数据，这些个体来自自我认定的非裔美国人、波多黎各人和墨西哥裔美国人。这些人群是欧洲、非洲和美洲原住民血统的三向混合，为研究按当地血统和 ROH 划分的有害等位基因的分布提供了机会。我们重申了之前的发现，即长 ROH 在全基因组范围内富含有害变异。然后，我们按当地血统进行划分，结果表明，当 ROH 与非洲血统片段重叠时，有害纯合子的出现率高于与基因组的欧洲或美洲原住民血统片段重叠时。这些结果表明，虽然任何单倍型背景上的ROH都与有害纯合变异的增加有关，但非洲单倍型背景可能在混合个体的复杂疾病的遗传结构中发挥特别重要的作用，这凸显了对这些群体进行进一步研究的必要性。
Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.