Competitive Repair by Naturally Dispersed Repetitive DNA during Non-Allelic Homologous Recombination
Open Access
- 2 December 2010
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 6 (12), e1001228
- https://doi.org/10.1371/journal.pgen.1001228
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. 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 non-allelic sites recombine during non-allelic homologous recombination (NAHR). Here we study NAHR on a genome-wide scale using the experimentally tractable budding yeast as a eukaryotic model genome with its fully sequenced family of repeated DNA elements, the Ty retrotransposons. With our novel system, we simultaneously measure the effects of known recombination parameters on the frequency of NAHR to understand which parameters most influence the occurrence of rearrangements between repetitive sequences. These findings provide a basic framework for interpreting how structural changes observed in the human genome may have arisen.Keywords
This publication has 53 references indexed in Scilit:
- A three-dimensional model of the yeast genomeNature, 2010
- Mitotic gene conversion events induced in G1-synchronized yeast cells by gamma rays are similar to spontaneous conversion eventsProceedings of the National Academy of Sciences of the United States of America, 2010
- Analysis of repair mechanism choice during homologous recombinationNucleic Acids Research, 2009
- L1 recombination-associated deletions generate human genomic variationProceedings of the National Academy of Sciences, 2008
- Double-strand breaks associated with repetitive DNA can reshape the genomeProceedings of the National Academy of Sciences, 2008
- Mapping and sequencing of structural variation from eight human genomesNature, 2008
- In Vivo Roles of Rad52, Rad54, and Rad55 Proteins in Rad51-Mediated RecombinationMolecular Cell, 2003
- Colocalization of multiple DNA double-strand breaks at a single Rad52 repair centreNature, 2003
- Sequencing and comparison of yeast species to identify genes and regulatory elementsNature, 2003
- Separation of yeast chromosome-sized DNAs by pulsed field gradient gel electrophoresisCell, 1984