Variation in proviral content among human genomes mediated by LTR recombination

Jainy Thomas,Hervé Perron,Cédric Feschotte

doi:10.1186/s13100-018-0142-3

Jainy Thomas, Hervé Perron + Show 1 more

Open Access

https://doi.org/10.1186/s13100-018-0142-3

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Abstract

BackgroundHuman 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Human endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences
The prediction is that a fraction of the read mates to the reads mapping to the annotated solo Long terminal repeat (LTR) should be derived from internal sequences of the provirus allele
The novel dimorphic candidate that we identified for HERV-K (5q11.2_K3) is predicted to be a provirus in 164 individuals and a maximum of six informative discordant reads are mapped to that locus in an individual (Additional file 2)

Summary

Introduction

Human endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. 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. Full-length (proviral) ERV insertions are comprised of two long terminal repeats (LTRs) flanking an internal region encoding the proteincoding genes necessary for retroviral replication and propagation, including gag (group antigens); pol (polymerase) and env (envelope) [1, 2]. Copy number variation represents a potent mechanism to create inter-individual differences in HERV expression [26], but the extent by which HERV genes vary in copy number across humans and how this variation relates to disease susceptibility remains understudied

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