Novel mutations in the Myo5a gene cause a dilute coat color phenotype in mice

C57BL/6 laboratory mice usually show black coat color. We observed a dilute (gray) coat color phenotype in progenies of two C57BL/6 mice. This phenotype is inherited in an autosomal recessive mode. To uncover the molecular mechanism underlying this naturally occurring phenotypic variation, we performed whole‐genome sequencing (25×) on 10 offspring of the two founder mice. The whole‐genome DNA sequencing and additional RNA‐Seq data reveal that Myo5a is the gene responsible for the coat color dilution in C57BL/6 mice, and novel mutations in the Myo5a gene are likely causal. We further performed reverse transcription‐quantitative PCR, and showed increased expression of truncated Myo5a transcripts encoding dysfunctional proteins and decreased expression of Myo5a full‐length transcripts encoding functional proteins in mutant individuals. The decrease in full‐length messenger RNA abundance was accompanied by reduced Myo5a protein level and deficient melanosome transport, a potential mechanistic link between the Myo5a mutations and the dilute color phenotype. This study not only advances our understanding of the molecular mechanisms of pigmentation in mice, but also provides a typical case of deciphering the molecular basis of phenotypic variation in mice by genomic analyses and subsequent functional work.