Abstract
BACKGROUND: Human endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. The vast majority of HERV sequences descend from ancient retroviral families no longer capable of infection or genomic propagation. In fact, most are no longer represented by full-length proviruses but by solitary long terminal repeats (solo LTRs) that arose via non-allelic recombination events between the two LTRs of a proviral insertion. Because LTR-LTR recombination events may occur long after proviral insertion but are challenging to detect in resequencing data, we hypothesize that this mechanism is a source of genomic variation in the human population that remains vastly underestimated. RESULTS: We developed a computational pipeline specifically designed to capture dimorphic proviral/solo HERV allelic variants from short-read genome sequencing data. When applied to 279 individuals sequenced as part of the Simons Genome Diversity Project, the pipeline retrieves most of the dimorphic loci previously reported for the HERV-K(HML2) subfamily as well as dozens of additional candidates, including members of the HERV-H and HERV-W families previously involved in human development and disease. We experimentally validate several of these newly discovered dimorphisms, including the first reported instance of an unfixed HERV-W provirus and an HERV-H locus driving a transcript (ESRG) implicated in the maintenance of embryonic stem cell pluripotency. CONCLUSIONS: Our findings indicate that human proviral content exhibit more extensive interindividual variation than previously recognized, which has important bearings for deciphering the contribution of HERVs to human physiology and disease. Because LTR retroelements and LTR recombination are ubiquitous in eukaryotes, our computational pipeline should facilitate the mapping of this type of genomic variation for a wide range of organisms.