Break-Induced Replication Is Highly Inaccurate

Deem, Angela K.; Keszthelyi, Andrea; Blackgrove, Tiffany; Vayl, Alexandra; Coffey, Barbara M.; Mathur, Ruchi; Chabes, Andrei; Malkova, Anna

doi:10.1371/journal.pbio.1000594

Cited by 267 publications

(300 citation statements)

References 69 publications

(114 reference statements)

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“…These replication-based mechanisms are hypothesized to be highly error prone (Carvalho et al 2013) because they utilize a low-fidelity polymerase enzyme, leading to an increased mutation load around the breakpoints. Other studies (Deem et al 2011;Arlt et al 2012) exploring replication mechanisms in organisms, such as mouse and yeast, also found high error rates and mutations.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 96%

Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis

Dhokarh

Abyzov

2016

Genome Res.

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Copy number variants (CNVs) are a class of structural variants that may involve complex genomic rearrangements (CGRs) and are hypothesized to have additional mutations around their breakpoints. Understanding the mechanisms underlying CNV formation is fundamental for understanding the repair and mutation mechanisms in cells, thereby shedding light on evolution, genomic disorders, cancer, and complex human traits. In this study, we used data from the 1000 Genomes Project to analyze hundreds of loci harboring heterozygous germline deletions in the subjects NA12878 and NA19240. By utilizing synthetic long-read data (longer than 2 kbp) in combination with high coverage short-read data and, in parallel, by comparing with parental genomes, we interrogated the phasing of these deletions with the flanking tens of thousands of heterozygous SNPs and indels. We found that the density of SNPs/indels flanking the breakpoints of deletions (in-phase variants) is approximately twice as high as the corresponding density for the variants on the haplotype without deletion (out-of-phase variants). This fold change was even larger for the subset of deletions with signatures of replication-based mechanism of formation. The allele frequency (AF) spectrum for deletions is enriched for rare events; and the AF spectrum for in-phase SNPs is shifted toward this deletion spectrum, thus offering evidence consistent with the concomitance of the in-phase SNPs/indels with the deletion events. These findings therefore lend support to the hypothesis that the mutational mechanisms underlying CNV formation are error prone. Our results could also be relevant for resolving mutation-rate discrepancies in human and to explain kataegis.

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Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 96%

Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis

Dhokarh

Abyzov

2016

Genome Res.

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“…There exists a perfect correlation between our allele assignment and that reported in sequence assembly 22. A snapshot of the raw data is shown in Figure S4.Loss of Heterozygosity in Candida albicans 1167 complicated patterns, in which some polymorphisms are detected, interspersed in the homozygous regions (alleles a for P21, P32, and P41, and alleles b for P27 and P29) and are indicative of complex recombination events or additional mutations (Hicks et al 2010;Deem et al 2011). It should be noted that P21, which exhibited the highest MMS sensitivity, also carries a Chr2L LOH event ( Figure 4 and Figure S3C; see below).…”

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confidence: 99%

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

et al. 2016

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By testing the susceptibility to DNA damaging agents of several Candida albicans mutant strains derived from the commonly used laboratory strain, CAI4, we uncovered sensitivity to methyl methanesulfonate (MMS) in CAI4 and its derivatives, but not in CAF2-1. This sensitivity is not a result of URA3 disruption because the phenotype was not restored after URA3 reintroduction. Rather, we found that homozygosis of a short region of chromosome 3R (Chr3R), which is naturally heterozygous in the MMS-resistant-related strains CAF4-2 and CAF2-1, confers MMS sensitivity and modulates growth polarization in response to MMS. Furthermore, induction of homozygosity in this region in CAF2-1 or CAF4-2 resulted in MMS sensitivity. We identified 11 genes by SNP/comparative genomic hybridization containing only the a alleles in all the MMS-sensitive strains. Four candidate genes, SNF5, POL1, orf19.5854.1, and MBP1, were analyzed by generating hemizygous configurations in CAF2-1 and CAF4-2 for each allele of all four genes. Only hemizygous MBP1a/mbp1b::SAT1-FLIP strains became MMS sensitive, indicating that MBP1a in the homo-or hemizygosis state was sufficient to account for the MMS-sensitive phenotype. In yeast, Mbp1 regulates G1/S genes involved in DNA repair. A second region of homozygosis on Chr2L increased MMS sensitivity in CAI4 (Chr3R homozygous) but not CAF4-2 (Chr3R heterozygous). This is the first example of sign epistasis in C. albicans.KEYWORDS Candida albicans; LOH; MMS susceptibility; MBP1; growth polarization T HE opportunistic fungal pathogen Candida albicans is often isolated as a highly heterozygous diploid; the genome of the reference strain SC5314 has 67,500 single nucleotide polymorphisms (SNPs) (Jones et al. 2004;Braun et al. 2005;Muzzey et al. 2013). SNPs found within regulatory regions can affect transcription levels between the alleles (Staib et al. 2002). Even synonymous SNPs residing in open reading frames (ORFS) can result in differences in the rate and efficiency of messenger RNA (mRNA) translation since poorly used codons delay protein synthesis. These delays may lead to misfolding of the nascent protein or formation of mRNA secondary structures (reviewed in Larriba and Calderone 2008). Recent genome-wide analysis of cis elements on gene expression showed that allele-specific effects are often due to mRNA levels and/or translation efficiency (Muzzey et al. 2014).While the majority of SNPs reside in intergenic regions, more than half of open reading frames contain one or more SNPs. The vast majority (78%) of these are nonsynonymous, implying that a significant fraction of ORFs encode proteins that differ in one or more amino acids (Jones et al. 2004) that may affect crucial properties. Nonconservative amino acid substitutions within an enzyme's catalytic domain could result in an inactive allele (Gómez-Raja et al. 2008). However, many SNPs will cause only minor or insignificant alterations in protein properties.Mitotic recombination or less frequently, chromosome truncation or loss, will reveal ...

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“…The discoordination between leading and lagging strand synthesis in BIR helps to explain why, as in gene conversion, there is a >1,000-fold elevation in mutations associated with BIR (19,115). In addition to "local" template switches leading to deletions in homonucleotide runs, BIR displays a high level of interchromosomal template jumps.…”

Section: Break-induced Replicationmentioning

confidence: 99%

A Life Investigating Pathways That Repair Broken Chromosomes

Haber

2016

Annu. Rev. Genet.

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Double-strand breaks (DSBs) pose a severe challenge to genome integrity; consequently, cells have developed efficient mechanisms to repair DSBs through several pathways of homologous recombination and other nonhomologous end-joining processes. Much of our understanding of these pathways has come from the analysis of site-specific DSBs created by the HO endonuclease in the budding yeast Saccharomyces cerevisiae. I was fortunate to get in on the ground floor of analyzing the fate of synchronously induced DSBs through the study of what I coined "in vivo biochemistry." I have had the remarkable good fortune to profit from the development of new techniques that have permitted an ever more detailed dissection of these repair mechanisms, which are described here.

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Break-Induced Replication Is Highly Inaccurate

Abstract: DNA replication initiated by one-ended homologous recombination at a double-strand break is highly inaccurate, as it greatly stimulates frameshift mutations over the entire path of the replication fork.

Cited by 267 publications

References 69 publications

Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis

Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication hypothesis

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

A Life Investigating Pathways That Repair Broken Chromosomes

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