Department of Biological Statistics & Computational Biology, Cornell University, Ithaca, NY, USA.
Nat Genet. 2013 Jul;45(7):723-9. doi: 10.1038/ng.2658. Epub 2013 Jun 9.
For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we use whole-genome sequences and genome-wide chromatin immunoprecipitation and sequencing data to demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4-6 million years ago. Our analysis uses a new probabilistic method, called INSIGHT, for measuring the influence of selection on collections of short, interspersed noncoding elements. We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease.
几十年来，人们一直假设基因调控在人类进化中起着核心作用，但对于调控突变对基因组范围的影响仍知之甚少。在这里，我们使用全基因组序列和全基因组染色质免疫沉淀和测序数据来证明，自 400 万至 600 万年前人类与黑猩猩分化以来，自然选择已经深刻地影响了人类转录因子结合位点。我们的分析使用了一种新的概率方法，称为 INSIGHT，用于测量选择对短的、分散的非编码元件集合的影响。我们发现，平均而言，转录因子结合位点经历的选择比蛋白质编码基因稍弱。然而，一些转录因子的结合位点显示出明显的适应证据。几种选择度量与预测的结合亲和力密切相关。总的来说，调节元件似乎对适应性替代和有害多态性都有很大贡献，这对人类进化和疾病具有重要意义。
