Genome-Wide Analysis of Natural Selection on Human Cis-Elements

BackgroundIt has been speculated that the polymorphisms in the non-coding portion of the human genome underlie much of the phenotypic variability among humans and between humans and other primates. If so, these genomic regions may be undergoing rapid evolutionary change, due in part to natural selection. However, the non-coding region is a heterogeneous mix of functional and non-functional regions. Furthermore, the functional regions are comprised of a variety of different types of elements, each under potentially different selection regimes.
Findings and ConclusionsUsing the HapMap and Perlegen polymorphism data that map to a stringent set of putative binding sites in human proximal promoters, we apply the Derived Allele Frequency distribution test of neutrality to provide evidence that many human-specific and primate-specific binding sites are likely evolving under positive selection. We also discuss inherent limitations of publicly available human SNP datasets that complicate the inference of selection pressures. Finally, we show that the genes whose proximal binding sites contain high frequency derived alleles are enriched for positive regulation of protein metabolism and developmental processes. Thus our genome-scale investigation provides evidence for positive selection on putative transcription factor binding sites in human proximal promoters.

研究背景
人们曾推测，人类基因组非编码区域的多态性（polymorphisms）是造成人类群体内部以及人类与其他灵长类动物之间表型变异的核心诱因之一。若该推测成立，那么此类基因组区域或正经历快速的演化改变，这在一定程度上由自然选择所驱动。然而，非编码区域是功能区域与非功能区域的异质性混合体；进一步而言，功能区域由多种不同类型的调控元件构成，每种元件可能面临潜在不同的选择模式。
研究结果与结论
本研究利用定位至人类近端启动子（proximal promoters）中一系列严格筛选的推定结合位点的HapMap与Perlegen多态性数据集，应用衍生等位基因频率分布中性检验（Derived Allele Frequency distribution test of neutrality），获得了大量人类特异性与灵长类特异性结合位点可能处于正向选择（positive selection）之下的证据。此外，本研究还探讨了公开可用的人类单核苷酸多态性（SNP, Single Nucleotide Polymorphism）数据集所固有的局限性，此类局限性会增加推断选择压力的复杂程度。最后，研究发现，近端结合位点携带高频衍生等位基因的基因，在蛋白质代谢的正向调控以及发育过程相关功能中显著富集。综上，本项全基因组范围的研究为人类近端启动子内推定转录因子结合位点（transcription factor binding sites）受到正向选择提供了科学证据。