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Add caveat about unannotated genes in interval.
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tomsasani committed Oct 24, 2023
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Expand Up @@ -64,8 +64,11 @@ This signal was specific to BXDs with *D* genotypes at the `rs27509845` locus, a
The peak markers on chromosome 4 and 6 did not exhibit strong linkage disequilibrium ($R^2$ = 4e-5).
We also performed QTL scans for the fractions of each 1-mer mutation type using the same mutation data, but none produced a genome-wide significant log-odds score at any locus (Figure {@fig:qtl-scans}; *Materials and Methods*).

We queried the region surrounding the top marker on chromosome 6 (+/- the 90% bootstrap confidence interval) and discovered 64 protein-coding genes, of which four were annotated with a Gene Ontology [@PMID:10802651;@PMID:33290552] term related to "DNA repair": *Fancd2*, *Ogg1*, *Setmar*, and *Rad18*.
Of these, two harbored nonsynonymous differences between the parental C57BL/6J and DBA/2J strains (Table @tbl:nonsyn-diffs).
We queried the region surrounding the top marker on chromosome 6 (+/- the 90% bootstrap confidence interval) and discovered 64 protein-coding genes, of which four were annotated with a Gene Ontology (GO) [@PMID:10802651;@PMID:33290552] term related to "DNA repair": *Fancd2*, *Ogg1*, *Setmar*, and *Rad18*.
None of the remaining genes were annotated with a cellular function that would obviously contribute to a germline mutator phenotype; however, many of these GO annotations are imperfect and/or incomplete.
Although we focus our analysis on DNA repair genes, it remains possible that other genes within the confidence interval could underlie the C>A mutator phenotype we identified in the BXDs.

Of the annotated DNA repair genes within the confidence interval, two harbored nonsynonymous differences between the parental C57BL/6J and DBA/2J strains (Table @tbl:nonsyn-diffs).
*Ogg1* encodes a key member of the base-excision repair response to oxidative DNA damage (a pathway that also includes *Mutyh*), and in mice *Setmar* encodes a SET domain-containing histone methyltransferase; both *Ogg1* and *Setmar* are expressed in mouse gonadal cells.
Because the bootstrap can exhibit poor coverage in QTL mapping studies [@PMID:16783000], we also scanned an interval +/- 5 Mbp from the peak AMSD marker on chromosome 6 for additional candidate genes.
Although the choice of a 10 Mbp interval is somewhat arbitrary, the interval does contain a plausible candidate: *Mbd4*, a protein-coding gene involved in base excision repair that also harbors a non-synonymous difference between the BXD parental strains (Table @tbl:nonsyn-diffs).
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