Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination

Abstract

BackgroundRecurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV).ResultsWe developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in ten individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9-mediated recombination hotspot motifs.ConclusionsThe presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements, such as long interspersed elements, may also be responsible for the formation of recurrent CNVs via NAHR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0074-4) contains supplementary material, which is available to authorized users.

Mechanisms underlying structural variant formation in genomic disorders

“…NAHR favours recombination between substrates that share perfect or near-perfect homology, as evidenced by the frequent use of LCRs ≥10 kb in length with ≥97% sequence identity 30 . Nonetheless, disease-causing rearrangements between repeat regions with a lower percentage of sequence identity occurs in some pathogenic CNVs (for example, HERV elements with 94–95% similarity 65–67 ). HERV-mediated CNVs show enrichment for PRDM9 hotspot motifs as well as the property of recurrence 65,67 , which suggests NAHR as their underlying mechanism.…”

Human Structural Variation: Mechanisms of Chromosome Rearrangements

“…Recombination between HERV elements can also give rise to recurrent CNVs. Deletions and duplications mediated by HERV–HERV recombination at three intrachromosomal loci were sequenced in a recent study [43]. Similarly to other HERV-mediated chromosome rearrangements [44–46], all the CNVs are flanked by HERV-H elements that are at least 3 kb in length and 93–96% identical.…”

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

“…However, the translocation partners are different chromosomes. Recombination between HERV-H repeats has been implicated in other translocations and deletions (Hermetz et al 2012;Shuvarikov et al 2013;Campbell et al 2014). Robberecht Case 7 has an unbalanced translocation likely mediated by NAHR between L1PA4 elements on Chromosomes 9 and 10.…”