Merge pull request #13 from quinlan-lab/elife_revisions

Major batch of changes for eLife revisions

content/01.abstract.md

@@ -8,8 +8,9 @@ DNA replication and repair proteins often recognize particular sequence motifs o
 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 [@PMID:35545679;@PMID:33472028].
 
-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 [@PMID:17581577;@PMID:10097147]. 
+> 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* [@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. 
 
 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. 

content/02.introduction.md

@@ -9,7 +9,7 @@ The dearth of observed germline mutators in mammalian genomes is not necessarily
 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, and mice [@doi:10.1101/2023.03.27.534460]. 
+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].
 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].
@@ -30,7 +30,8 @@ For example, performing association tests on the rates or fractions of every $k$
 Since germline mutation rates are generally quite low, estimates of $k$-mer mutation type frequencies from individual samples can also be noisy and imprecise.
 We were therefore motivated to develop a statistical method that could overcome the sparsity of *de novo* mutation spectra, eliminate the need to test each $k$-mer mutation type separately, and enable sensitive detection of alleles that influence the germline mutation spectrum.
 
-Here, we present a new mutation spectrum association test, called "inter-haplotype distance," that minimizes multiple testing burdens and mitigates the challenges of sparsity in *de novo* mutation datasets. 
+> Here, we present a new mutation spectrum association test, called "aggregate mutation spectrum distance," that minimizes multiple testing burdens and mitigates the challenges of sparsity in *de novo* mutation datasets. 
+
 We leverage this method to re-analyze germline mutation data from the BXD family and find compelling evidence for a second mutator allele that was not detected using previous approaches. 
 The new allele appears to interact epistatically with the mutator that was previously discovered in the BXDs, further augmenting the C>A germline mutation rate in a subset of inbred mice. 
 Our observation of epistasis suggests that mild DNA repair deficiencies can compound one another, as mutator alleles chip away at the redundant systems that collectively maintain germline integrity.