Long Runs of Homozygosity Are Enriched for Deleterious Variation
Long Runs of Homozygosity Are Enriched for Deleterious Variation
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DOI：
10.1016/j.ajhg.2013.05.003
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Li, Jun Z.
中科院分区：
文献类型：
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作者：
Szpiech, Zachary A.;Xu, Jishu;Li, Jun Z.
外显子组测序提供了研究有害变异模式背后的群体基因组变量的可能性。纯合游程(ROH)是连续纯合基因的长条延伸，可能反映由于血缘关系、种群规模减少和自然选择等过程而由血统分享的相同片段。ROH和预测的有害变异模式之间的关系可以洞察这些过程如何有助于有害变异的维持。在这里，我们使用外显子组测序来检查ROH与有害变异的分布之间的关系，这些个体来自6个人类群体，其中27个个体具有不同程度的明显近亲繁殖。在所有全基因组预测的损害性纯合子中，发生ROH的比例比预期的相应比例的非损伤性纯合子在ROH中下降的比例要大得多(p<；0.001)。这一模式在长期净资产收益率中最为明显(p<；0.05)。ROH，尤其是长ROH，比基于基因组的总ROH覆盖率和非破坏性纯合子的基因组分布而预期的有害纯合子不成比例地多。结果与一个假设一致，即最近的近亲繁殖产生了长ROH，使得罕见的有害变异能够以纯合子的形式存在。因此，就像近亲交配会增加罕见的隐性疾病的发生一样，近亲交配也会放大轻微有害变异的发生。
Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these processes contribute to the maintenance of deleterious variants. Here, we use exome sequencing to examine ROH in relation to the distribution of deleterious variation in 27 individuals of varying levels of apparent inbreeding from 6 human populations. A significantly greater fraction of all genome-wide predicted damaging homozygotes fall in ROH than would be expected from the corresponding fraction of nondamaging homozygotes in ROH (p < 0.001). This pattern is strongest for long ROH (p < 0.05). ROH, and especially long ROH, harbor disproportionately more deleterious homozygotes than would be expected on the basis of the total ROH coverage of the genome and the genomic distribution of nondamaging homozygotes. The results accord with a hypothesis that recent inbreeding, which generates long ROH, enables rare deleterious variants to exist in homozygous form. Thus, just as inbreeding can elevate the occurrence of rare recessive diseases that represent homozygotes for strongly deleterious mutations, inbreeding magnifies the occurrence of mildly deleterious variants as well.