NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117456, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.
Am J Hum Genet. 2013 Jun 6;92(6):866-81. doi: 10.1016/j.ajhg.2013.04.021. Epub 2013 May 23.
Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long-range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event.
自然选择是一种重要的力量，它塑造了人类基因组的结构，并在全球人群中引入了多样性。除了少数几个基因（如乳糖耐受基因、影响皮肤色素沉着的基因或导致镰状细胞贫血的基因）之外，人类基因组中是否由于单一或多次突变事件而产生有利突变的问题仍然没有答案。我们开发了一种长程单倍型方法来识别正选择的基因组特征，以补充现有的方法，如综合单倍型评分（iHS）或跨群体扩展单倍型纯合性（XP-EHH），以定位整个等位基因频率谱中的信号。我们的方法还定位携带有利变异的起始单倍型，并推断它们的相应种群频率。这为我们提供了一个机会，可以系统地研究整个人类基因组，以确定在不同人群中共享的选择信号是由于单一的突变过程随后发生的基因流，还是由于多个独立的突变事件在同一变异或同一基因中发生而导致的趋同进化的结果。将我们的方法应用于来自世界各地的 14 个人群的数据表明，正选择事件往往聚集在具有相同祖先的人群中。比较在不同人群中存在的事件的起始单倍型表明，趋同进化是罕见的，大多数共享信号源于同一进化事件。
