Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection.
Excess of Deleterious Mutations around HLA Genes Reveals Evolutionary Cost of Balancing Selection.
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DOI：
10.1093/molbev/msw127
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发表时间：
2016-10
影响因子：
10.7
通讯作者：
Sunyaev SR
中科院分区：
文献类型：
--
作者：
Lenz TL;Spirin V;Jordan DM;Sunyaev SR
有害的突变预计将在负选择下进化，通常会从种群中清除。然而，有害的等位基因在人群中分离，并且一些疾病相关的变体以相当高的频率维持。在这里，我们测试的假设，平衡选择可能会抵消净化选择在邻近地区，从而保持有害的变种在更高的频率比预期的有害健身效果。我们首先表明，在现实的模拟，平衡选择减少了密度的多态性位点周围的平衡选择下的基因座，但在同一时间显着增加了人口的频率，其余的变种，甚至包括实质上有害的等位基因。为了测试我们的模拟预测经验，我们然后使用来自6,500个人类个体的全外显子组测序数据，并专注于人类基因组中最成熟的平衡选择的例子，主要组织相容性复合体（MHC）。我们的分析表明，在非人类白细胞抗原（非HLA）基因定位在MHC区域的pupperimeter有害的编码变异的频率升高。这些变体的平均频率随着与经典HLA基因的物理距离而下降，表明依赖于遗传连锁。这些结果揭示了平衡选择所维持的遗传多样性的间接成本，这迄今为止被认为是最有利的，并且对重组的进化和各种MHC相关疾病的流行病学都有影响。
Deleterious mutations are expected to evolve under negative selection and are usually purged from the population. However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies. Here, we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect. We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles. To test the predictions of our simulations empirically, we then use whole-exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC). Our analysis shows an elevated frequency of putatively deleterious coding variants in nonhuman leukocyte antigen (non-HLA) genes localized in the MHC region. The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage. These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.
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影响因子：
3.9
作者：
Furlong, Rebecca F.;Yang, Ziheng
通讯作者：
Yang, Ziheng
DOI：
10.1073/pnas.1424949112
发表时间：
2015-05-19
影响因子：
11.1
作者：
Assaf, Zoe June;Petrov, Dmitri A.;Blundell, Jamie R.
通讯作者：
Blundell, Jamie R.
影响因子：
64.8
作者：
Bustamante, CD;Fledel-Alon, A;Clark, AG
通讯作者：
Clark, AG
影响因子：
3.3
作者：
Albrechtsen, Anders;Moltke, Ida;Nielsen, Rasmus
通讯作者：
Nielsen, Rasmus
影响因子：
3.3
作者：
Bubb, K. L.;Bovee, D.;Olson, M. V.
通讯作者：
Olson, M. V.