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. Recent studies of human genetic variation have revealed that, in addition to differing at single nucleotide polymorphisms, individuals differ in copy-number at many regions of the genome. These copy-number variants (CNVs) are caused by duplication or deletion events and often affect functional sequences such as genes. Efforts to reveal the functional impact of CNVs have identified many variants increasing the risk of various disorders, and some that are adaptive. However, these studies mostly fail to detect gene duplications caused by retrotransposition, in which an mRNA transcript is reverse-transcribed and reinserted into the genome, yielding a new intron-less gene copy. Here we describe a method leveraging next-generation sequence data to accurately detect gene copy-number variants caused by retrotransposition, or retroCNVs, and apply this method to hundreds of whole-genome sequences from three different human subpopulations. We find that these variants account for a substantial number of gene copy-number differences between individuals, and that gene retrotransposition may often result in both deleterious and beneficial mutations. Indeed, we present evidence that two of these new gene duplications may be adaptive. These results imply that retroCNVs are an especially important class of CNV and should be included in future studies of human copy-number variation.