Zoology Faculty Work
Title
A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the MiniMuscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice
Document Type
Article
Publication Date
2013
Publication Title
Genetics
Volume Number
195
Issue Number
4
DOI
10.1534/genetics.113.154476
Abstract
Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing ∼100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4Minimsc. Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics.
ISSN
1943-2631
First Page
1385
Last Page
1395
Recommended Citation
Kelly, Scott; Bell, Timothy; Selitsky, Sara; Buus, Ryan; Hua, Kunjie; Weinstock, George; Garland, Theodore; Pardo-Manuel de Villena, Fernando; and Pomp, Daniel, "A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the MiniMuscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice" (2013). Zoology Faculty Work. 12.
https://digitalcommons.owu.edu/zool_pubs/12
Link Out URL
https://doi.org/10.1534/genetics.113.154476