Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the Factor VII locus in humans
Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the Factor VII locus in humans
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DOI：
10.1534/genetics.103.025726
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发表时间：
2004-06-01
期刊：
影响因子：
3.3
通讯作者：
Wray, GA
中科院分区：
文献类型：
--
作者：
Hahn, MW;Rockman, MV;Wray, GA
人类中丰富的顺式调控基因多态性表明，许多基因可能在人类进化中发挥了重要作用，但有关它们作用的证据相对较少。凝血因子VII(F7)5‘端启动子区的四个常见多态在体外和体内都会影响其转录和蛋白丰度。这些多态中有三个具有降低F7表达的低频等位基因，并可能提供对心肌梗死(心脏病发作)的保护。第四种多态有一个微小的等位基因，可以提高转录水平。为了寻找F7两侧顺式调控变体上自然选择的证据，我们对六个旧大陆群体中的三个多态基因进行了基因分型，我们也有一组假定为中性的SNPs的数据。我们的群体遗传分析显示，有证据表明人类内部存在选择；令人惊讶的是，最有力的证据是新加坡华人高表达变异的频率大幅增加。对日本人群的进一步表征表明，至少在其他东亚人群中发现了高表达等位基因频率的增加的一部分。此外，为了检验种间选择模式，我们对黑猩猩、矮黑猩猩、大猩猩、猩猩和狒狒的同源5‘非编码区进行了测序。对这些数据的分析揭示了人类谱系中转录因子结合位点的过度固定差异。因此，我们的结果进一步支持了这样的假设，即调节突变在人类进化中是重要的。
The abundance of cis-regulatory polymorphisms in humans Suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, bave been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisins in six Old World populations for which we also have data front a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is clue to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.