Abstract
Genome rearrangements often result from non-allelic homologous recombination (NAHR) between repetitive DNA elements dispersed throughout the genome. Here we systematically analyze NAHR between Ty retrotransposons using a genome-wide approach that exploits unique features of Saccharomyces cerevisiae purebred and Saccharomyces cerevisiae/Saccharomyces bayanus hybrid diploids. We find that DNA double-strand breaks (DSBs) induce NAHR–dependent rearrangements using Ty elements located 12 to 48 kilobases distal to the break site. This break-distal recombination (BDR) occurs frequently, even when allelic recombination can repair the break using the homolog. Robust BDR–dependent NAHR demonstrates that sequences very distal to DSBs can effectively compete with proximal sequences for repair of the break. In addition, our analysis of NAHR partner choice between Ty repeats shows that intrachromosomal Ty partners are preferred despite the abundance of potential interchromosomal Ty partners that share higher sequence identity. This competitive advantage of intrachromosomal Tys results from the relative efficiencies of different NAHR repair pathways. Finally, NAHR generates deleterious rearrangements more frequently when DSBs occur outside rather than within a Ty repeat. These findings yield insights into mechanisms of repeat-mediated genome rearrangements associated with evolution and cancer.
Highlights
Human structural variation contributes to phenotypic differences and susceptibility to disease [1]
allelic homologous recombination (AHR) and non-allelic homologous recombination (NAHR) are both initiated by a double-strand break (DSB) that is processed by 59-39 DNA resection to generate 39-OH tailed singlestranded DNA intermediates [6]
The human genome is structurally dynamic, frequently undergoing loss, duplication, and rearrangement of large chromosome segments. These structural changes occur both in normal and in cancerous cells and are thought to cause both benign and deleterious changes in cell function. Many of these structural alterations are generated when two dispersed repeated DNA sequences at nonallelic sites recombine during non-allelic homologous recombination (NAHR)
Summary
Human structural variation contributes to phenotypic differences and susceptibility to disease [1]. Recent studies suggest that many structural variants are mediated by non-allelic homologous recombination (NAHR) between dispersed repetitive DNA elements [2,3,4,5]. NAHR ( known as ectopic recombination) utilizes the molecular pathways that mediate allelic homologous recombination (AHR) between sister chromatids or homologs. If the recipient is unique DNA, the donor will be the homolog or sister chromatid, and AHR ensues. If the recipient is repetitive DNA, it may choose a non-allelic repeat as a donor, leading to NAHR and potentially a chromosome rearrangement. The establishment of this basic recipient-donor partnership during homologous recombination (HR) defines four fundamental parameters for NAHR that we address here
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