A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice
- Mikhail O. Maksimov1,2,12,
- Cynthia Wu3,12,
- David G. Ashbrook4,
- Flavia Villani4,
- Vincenza Colonna4,5,
- Nima Mousavi6,
- Nichole Ma1,
- Lu Lu4,
- Jonathan K. Pritchard7,8,
- Alon Goren1,9,
- Robert W. Williams4,
- Abraham A. Palmer9,10 and
- Melissa Gymrek1,2,9,11
- 1Department of Medicine, University of California San Diego, La Jolla, California 92093, USA;
- 2Department of Computer Science and Engineering, University of California San Diego, La Jolla, California 92093, USA;
- 3Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California 92093, USA;
- 4Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA;
- 5Institute of Genetics and Biophysics, National Research Council, Naples 80111, Italy;
- 6Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, California 92093, USA;
- 7Department of Genetics, Stanford University, Stanford, California 94305, USA;
- 8Department of Biology, Stanford University, Stanford, California 94305, USA;
- 9Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA;
- 10Department of Psychiatry, Department of Medicine, University of California San Diego, La Jolla, California 92093, USA;
- 11Department of Biomedical Informatics,
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↵12 These authors contributed equally to this work.
Abstract
Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1–6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5′ end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression—with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.277576.122.
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Freely available online through the Genome Research Open Access option.
- Received December 8, 2022.
- Accepted April 26, 2023.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
