Epistasis between mutator alleles contributes to germline mutation rate variability in laboratory mice

Author:

Sasani Thomas A.1ORCID,Quinlan Aaron R.2ORCID,Harris Kelley3ORCID

Affiliation:

1. Department of Human Genetics, University of Utah

2. Department of Human Genetics, University of Utah; Department of Biomedical Informatics, University of Utah · Funded by NIH/NHGRI R01HG012252

3. Department of Genome Sciences, University of Washington · Funded by NIH/NIGMS R35GM133428; Burroughs Wellcome Career Award at the Scientific Interface; Searle Scholarship; Pew Scholarship; Sloan Fellowship; Allen Discovery Center for Cell Lineage Tracing

Abstract

Maintaining germline genome integrity is essential and enormously complex. Hundreds of proteins are involved in DNA replication and proofreading, and hundreds more are mobilized to repair DNA damage [1]. While loss-of-function mutations in any of the genes encoding these proteins might lead to elevated mutation rates, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize particular sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations — that is, the frequency of each individual mutation type (C>T, A>G, etc.) — will differ between genomes that harbor either a mutator or wild-type allele at a given locus. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs [2, 3]. In this study we developed a new method, called “inter-haplotype distance,” to detect alleles associated with mutation spectrum variation. By applying this approach to mutation data from the BXDs, we confirmed the presence of the germline mutator locus near Mutyh and discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1 and Mbd4, two DNA glycosylases involved in base-excision repair [4, 5]. The effect of a chromosome 6 mutator allele depended on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci had even greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles, and may be applicable to mutation data from humans and other model organisms.

Publisher

eLife Sciences Publications, Ltd

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3