Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae

Genetics
Peter C StirlingPhilip Hieter

Abstract

In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13-Stn1-Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target ...Continue Reading

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Citations

Sep 29, 2015·DNA Repair·John J Wyrick, Steven A Roberts
Sep 2, 2015·Briefings in Functional Genomics·Vivien Measday, Peter C Stirling
May 6, 2015·Trends in Genetics : TIG·Romulo SegoviaPeter C Stirling
Oct 19, 2016·Basic & Clinical Pharmacology & Toxicology·Maria ZhivaguiJiri Zavadil
Oct 19, 2017·The Journal of Cell Biology·Emily Yun-Chia ChangPeter C Stirling
Oct 6, 2017·The Journal of Cell Biology·Veena MathewPeter C Stirling
Feb 7, 2019·Nucleus·Karissa L MilburyPeter C Stirling
May 11, 2018·BMC Genomics·Adam B BurkholderDavid C Fargo
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Romulo SegoviaPeter C Stirling

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Methods Mentioned

BETA
deamination

Software Mentioned

Integrated Genomics Viewer
Integrative Genomics Viewer
CNAseq
Burrows Aligner
SnpEff
ImageJ
SAMtools
FALCOR

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