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content/02.introduction.md

@@ -5,13 +5,13 @@ For example, parental age is an important determinant of mutation rate variabili
 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 [@PMID:27739533].
+The dearth of observed germline mutators in mammalian genomes is not necessarily surprising, since alleles that lead to elevated germline mutation rates likely have deleterious consequences and are likely to be purged by negative selection if their effect sizes are large [@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 [@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 [@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].
+Other groups have observed mutator phenotypes in the germlines and somatic tissues of adults who carry cancer-predisposing inherited mutations in the POLE/POLD1 exonucleases [@PMID:34594041;@PMID:37336879].
 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 [@PMID:35545679].
@@ -20,7 +20,7 @@ The BXDs were maintained via brother-sister mating for up to 180 generations, an
 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 [@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.
+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. Pathogenic variants of *Mutyh* also appear to act as mutators in normal human germline and somatic tissues [@PMID:35803914;@PMID:30753674].
 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 [@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).