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bioRxiv · 10.1101/2022.03.02.482700

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice

Maksimov, M.·Ashbrook, D. G.·BXD Sequencing Consortium,·Villani, F.·Colonna, V.·Mousavi, N.·Ma, N.·Palmer, A. A.·Gymrek, M.
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Abstract

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements characterized by repeated units of 1 or more nucleotides. We leveraged whole genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family derived from C57BL/6J and DBA/2J mice to study the effects of genetic background on genome-wide patterns of new mutations at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and identified a locus on chromosome 13 associated with the propensity of STRs to expand. Several dozen genes lie in the QTL region, including Msh3, a known modifier of STR stability at pathogenic repeat expansions in mice and humans. Detailed analysis of the locus revealed a cluster of variants near the 5 end of Msh3, including multiple protein-coding variants within the DNA mismatch recognition domain of MSH3, and a retrotransposon insertion overlapping an annotated exon. Additionally, gene expression analysis demonstrates co-localization of this QTL with expression QTLs for multiple nearby genes, including Msh3. Our results suggest a novel role for Msh3 in regulating genome-wide patterns of germline STR mutations and demonstrate that inherited genetic variation can contribute to variability in accumulation of new mutations across individuals.

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Maksimov, M., Ashbrook, D. G., BXD Sequencing Consortium,, Villani, F., Colonna, V., Mousavi, N., Ma, N., Palmer, A. A., Gymrek, M.. 2022-03-02. A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice. https://doi.org/10.1101/2022.03.02.482700

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