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Single SNP in a myosin gene identified as the source of the mini-muscle phenotype

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DOI:10.1038/bonekey.2014.42

Kelly et al. combined the latest methods available in genomics with an experiment in evolution that began in 1993 to reveal important insights into how a minor genetic variant can have a major effect on phenotype.

The initial work selected mice from a wild-type population that showed a high level of voluntary wheel running. Successive inbreeding over 28 generations produced High-Runner lines of mice that ran >70% more wheel revolutions per day compared with controls. Characterizing the mice revealed that an autosomal recessive mutation had been artificially selected, resulting in a mini-muscle phenotype. Mice had a much reduced muscle mass in the hind limbs with longer hind limb bones.

This study narrowed the location of the Minimsc locus to a region of the mouse genome with around 100 predicted or known genes. Whole-genome sequencing combined with high-density genotyping revealed a mutation in the myosin, heavy polypeptide 4, skeletal muscle gene (Myh4), caused by a C to T transition in a 709-bp intron, located between exon 11 and exon 12.

Editor’s comment: The Myh4-Minimsc allele exhibits classical properties of a gene of major effect, including its Mendelian recessive nature, dramatic effect on phenotype (muscle mass), and pleiotropic effects. This strategy could be used to characterize other causative mutations in mouse lines generated by inbreeding.

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