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content/01.abstract.md

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 ## Abstract {.page_break_before}
 
 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 [@pubmed:28485537]. 
+Hundreds of proteins are involved in DNA replication and proofreading, and hundreds more are mobilized to repair DNA damage [@PMID:28485537]. 
 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 [@pubmed:35545679;@pubmed:33472028].
+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 [@PMID:35545679;@PMID:33472028].
 
 > In this study we developed a new method, called "aggregate mutation spectrum 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*, a DNA glycosylase involved in the same base-excision repair network as *Mutyh* [@pubmed:17581577].
+> 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*, a DNA glycosylase involved in the same base-excision repair network as *Mutyh* [@PMID:17581577].
 
 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. 
 

content/02.introduction.md

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 ## Introduction
 
 Germline mutation rates reflect the complex interplay between DNA proofreading and repair pathways, exogenous sources of DNA damage, and life-history traits. 
-For example, parental age is an important determinant of mutation rate variability; in many mammalian species, the number of germline *de novo* mutations observed in offspring increases as a function of paternal and maternal age [@pubmed:28959963;@pubmed:31549960;@pubmed:35771663;@pubmed:32804933;@pubmed:31492841].
-Rates of germline mutation accumulation are also variable across human families [@pubmed:26656846;@pubmed:31549960], likely due to either genetic variation or differences in environmental exposures.
+For example, parental age is an important determinant of mutation rate variability; in many mammalian species, the number of germline *de novo* mutations observed in offspring increases as a function of paternal and maternal age [@PMID:28959963;@PMID:31549960;@PMID:35771663;@PMID:32804933;@PMID:31492841].
+Rates of germline mutation accumulation are also variable across human families [@PMID:26656846;@PMID:31549960], likely due to either genetic variation or differences in environmental exposures.
 Although numerous protein-coding genes contribute to the maintenance of genome integrity, genetic variants that increase germline mutation rates, known as *mutator alleles*, have proven difficult to discover in mammals.
 
-The dearth of observed germline mutators in mammalian genomes is not necessarily surprising, since alleles that lead to elevated germline mutation rates would likely have deleterious consequences and be purged by negative selection [@pubmed:27739533].
+The dearth of observed germline mutators in mammalian genomes is not necessarily surprising, since alleles that lead to elevated germline mutation rates would likely have deleterious consequences and be purged by negative selection [@PMID:27739533].
 Moreover, germline mutation rates are relatively low, and direct mutation rate measurements require whole-genome sequencing data from both parents and their offspring.
-As a result, large-scale association studies — which have been used to map the contributions of common genetic variants to many complex traits — are not currently well-powered to investigate the polygenic architecture of germline mutation rates [@pubmed:31964835].  
+As a result, large-scale association studies — which have been used to map the contributions of common genetic variants to many complex traits — are not currently well-powered to investigate the polygenic architecture of germline mutation rates [@PMID:31964835].  
 
 Despite these challenges, less traditional strategies have been used to identify a small number of mutator alleles in humans, macaques [@doi:10.1101/2023.03.27.534460], and mice. 
-By focusing on families with rare genetic diseases, a recent study discovered two mutator alleles that led to significantly elevated rates of *de novo* germline mutation in human genomes [@pubmed:35545669]. 
-Another group observed mutator phenotypes in the sperm and somatic tissues of adults who carry cancer-predisposing inherited mutations in the POLE/POLD1 exonucleases [@pubmed:34594041].
-Candidate mutator loci were also found by identifying human haplotypes from the Thousand Genomes Project with excess counts of derived alleles in genomic windows [@pubmed:28095480].
+By focusing on families with rare genetic diseases, a recent study discovered two mutator alleles that led to significantly elevated rates of *de novo* germline mutation in human genomes [@PMID:35545669]. 
+Another group observed mutator phenotypes in the sperm and somatic tissues of adults who carry cancer-predisposing inherited mutations in the POLE/POLD1 exonucleases [@PMID:34594041].
+Candidate mutator loci were also found by identifying human haplotypes from the Thousand Genomes Project with excess counts of derived alleles in genomic windows [@PMID:28095480].
 
-In mice, a germline mutator allele was recently discovered by sequencing a large family of inbred mice [@pubmed:35545679].
-Commonly known as the <u>B</u>X<u>D</u>s, these recombinant inbred lines (RILs) were derived from either F2 or advanced intercrosses of C57<u>B</u>L/6J and <u>D</u>BA/2J, two laboratory strains that exhibit significant differences in their germline mutation spectra [@pubmed:33472028;@pubmed:30753674]. 
+In mice, a germline mutator allele was recently discovered by sequencing a large family of inbred mice [@PMID:35545679].
+Commonly known as the <u>B</u>X<u>D</u>s, these recombinant inbred lines (RILs) were derived from either F2 or advanced intercrosses of C57<u>B</u>L/6J and <u>D</u>BA/2J, two laboratory strains that exhibit significant differences in their germline mutation spectra [@PMID:33472028;@PMID:30753674]. 
 The BXDs were maintained via brother-sister mating for up to 180 generations, and each BXD therefore accumulated hundreds or thousands of germline mutations on a nearly-homozygous linear mosaic of parental <u>B</u> and <u>D</u> haplotypes. 
 Due to their husbandry in a controlled laboratory setting, the BXDs were largely free from confounding by environmental heterogeneity, and the effects of selection on *de novo* mutations were attenuated by strict inbreeding [@doi:10.1146/annurev.ecolsys.39.110707.173437]. 
 
-In this previous study, whole-genome sequencing data from the BXD family were used to map a quantitative trait locus (QTL) for the C>A mutation rate [@pubmed:35545679].
+In this previous study, whole-genome sequencing data from the BXD family were used to map a quantitative trait locus (QTL) for the C>A mutation rate [@PMID:35545679].
 Germline C>A mutation rates were nearly 50% higher in mice with *D* haplotypes at the QTL, likely due to genetic variation in the DNA glycosylase *Mutyh* that reduced the efficacy of oxidative DNA damage repair.
 Importantly, the QTL did not reach genome-wide significance in a scan for variation in overall germline mutation rates, which were only modestly higher in BXDs with *D* alleles, demonstrating the utility of mutation spectrum analysis for mutator allele discovery.
-Close examination of the mutation spectrum is likely to be broadly useful for detecting mutator alleles, as genes involved in DNA proofreading and repair often recognize particular sequence motifs or excise specific types of DNA lesions [@pubmed:32619789].
+Close examination of the mutation spectrum is likely to be broadly useful for detecting mutator alleles, as genes involved in DNA proofreading and repair often recognize particular sequence motifs or excise specific types of DNA lesions [@PMID:32619789].
 Mutation spectra are usually defined in terms of $k$-mer nucleotide context; the 1-mer mutation spectrum, for example, consists of 6 mutation types after collapsing by strand complement (C>T, C>A, C>G, A>T, A>C, A>G), while the 3-mer mutation spectrum contains 96 (each of the 1-mer mutations partitioned by trinucleotide context).
 
 Although mutation spectrum analysis can enable the discovery of mutator alleles that affect the rates of specific mutation types, early implementations of this strategy have suffered from a few drawbacks.