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

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.

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

“…These called variants can become molecular phenotypes, which themselves can be mapped to causal loci. For example, we are able to identify genes causing specific mutation signatures 35,36 , and a loci influencing the number of SINE in the genome. We give a brief overview of some of these analyses here, but they are an interesting and important outcome in and of themselves, and will provide fuel for future research.…”

“…A subset of variants are unique to BXD epochs, due to shared parentage. The variation in generations of full sib mating makes it possible to estimate mutation rates and spectra with high precision—so high that we can even map loci that control mutation rates and properties 35,36 . BXD progeny with extreme phenotypes can be caused by polygenic interactions, but in a number of cases are due to the impact of de novo variants—for example, blindness in the BXD24-Cep90 line 26–28 .…”

The rate of spontaneous mutations in yeast deficient for MutSβ function

“…Mutations in the MMR complexes, especially MutSα, play a key role in certain cancers, and are the primary genetic basis of Lynch syndrome, which results in a high rate of colorectal, endometrial, and other cancers (Heinen 2016). Natural variants in MSH3 also influence the rate of SSR germline mutations in mice (Maksimov et al 2022) and the severity and age of onset of two diseases caused by SSR expansions in humans, Huntington Disease and Myotonic Dystrophy Type 1 (Flower et al 2019). Many studies have examined the role of MMR complexes in SSR mutation repair using reporter constructs in which an SSR precedes a reporter gene in yeast, such that SSR indels result in a selectable phenotypic readout (e.g.…”

The rate of spontaneous mutations in yeast deficient for MutSβ function

“…Mutations in the MMR complexes, especially MutSα, play a key role in certain cancers, and are the primary genetic basis of Lynch syndrome, which results in a high rate of colorectal, endometrial, and other cancers (Heinen 2016). Natural variants in MSH3 also influence the rate of SSR germline mutations in mice (Maksimov et al . 2022) and the severity and age of onset of two diseases caused by SSR expansions in humans, Huntington Disease and Myotonic Dystrophy Type 1 (Flower et al .…”

“…Mutations in the MMR complexes, especially MutSα, play a key role in certain cancers, and are the primary genetic basis of Lynch syndrome, which results in a high rate of colorectal, endometrial, and other cancers (Heinen 2016). Natural variants in MSH3 also influence the rate of SSR germline mutations in mice (Maksimov et al 2022) and the severity and age of onset of two diseases caused by SSR expansions in humans, Huntington Disease and Myotonic Dystrophy Type 1 (Flower et al 2019).Many studies have examined the role of MMR complexes in SSR mutation repair using reporter constructs in which an SSR precedes a reporter gene in yeast, such that SSR indels result in a selectable phenotypic readout (e.g. (Strand et al 1993(Strand et al , 1995 and others).…”