Natural Selection on Functional Modules, a Genome-Wide Analysis

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.传统上，基因组自然选择的功能后果，一直被拆解为单个基因的复合效应进行分析。当前用于大规模适应性演化分析的研究范式，基于观测到的单个基因进化速率与中性进化预期之间的显著偏差。这种假设基因间相互独立的研究方法，无法在单个物种中识别出显著富集于正选择基因的生物学功能。作为替代方案，整合近缘物种的数据能够增强选择印记的搜寻效率，但对物种进行分组后，却无法检验不同物种间的适应性差异。本文提出了基因集选择分析（Gene-Set Selection Analysis, GSSA）——一种全新的全基因组研究方法，用于检验功能模块上的自然选择证据。GSSA能够在大量功能模块中检测到谱系特异性的进化速率变化。例如，在9种哺乳动物和果蝇属物种的基因组中，GSSA识别出了数百个与进化速率高低存在显著关联的功能模块。诸多被检测到的进化速率偏高的功能模块，此前已被证实为受正选择作用的生物学功能。值得注意的是，GSSA还识别出了包含大量正选择基因的保守功能模块，这对“此类模块仅为适配环境变化而被选择”的观点提出了质疑。本研究结果与此前的研究结论一致：适应性演化需要正选择作用，但并非所有处于正选择下的突变，都能参与物种演化的适应性动态过程。