Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans

The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance.

全基因组测序时代已然揭示，由复制与缺失事件引发的基因拷贝数改变，具有重要的进化、功能及表型效应。因此，近期研究聚焦于解析人类及其他物种自然种群内的拷贝数变异程度。这些研究已在人类中发现大量拷贝数变异（copy-number variants, CNVs），其中诸多变异已被证实具有临床或进化层面的重要意义。但在绝大多数情况下，此类研究未能检测到一类重要的基因拷贝数多态性：由逆转座引发的基因复制——这类复制会将亲本基因的无内含子新拷贝插入基因组的随机位点。本研究描述了一种利用下一代测序数据检测逆转座引发的基因拷贝数变异（retroCNVs）的计算方法，并首次报道了人类群体中这类变异的全基因组分析结果。我们发现，任意两名个体间的基因拷贝数差异中，有相当一部分源自逆转座CNVs。此外，我们证实这类变异往往可产生表达型嵌合转录本，凸显了其在新基因功能进化中的潜在价值。通过定位这些复制拷贝的插入位点，我们证实逆转座CNVs在近期人类适应过程中发挥了重要作用，同时还发现了正选择正推动多个逆转座CNVs趋向固定的证据。综上，这些研究结果表明，逆转座CNVs是一类尤为重要的多态性变异，未来针对拷贝数变异的研究应当纳入这类变异的检测，以阐明其在进化与功能层面的潜在相关性。