Phylogeographic study using nuclear genome sequences of Asip to infer the origins of ventral fur color variation in the house mouse Mus musculus

Genes Genet Syst. 2022 Apr 21;96(6):271-284. doi: 10.1266/ggs.21-00075. Epub 2022 Mar 11.


While the house mouse (Mus musculus), widely distributed in Eurasia, is known to have substantial coat color variation between and within local populations, in both primary and secondary distribution areas, including the Japanese archipelago, the evolutionary history of the color variation is poorly understood. To address the ventral fur color variation, we quantified the lightness of museum skin specimens, and found that the southern subspecies, M. m. castaneus (CAS), has high and low lightness in dry and rainy geographic regions, respectively. The northern subspecies, M. m. musculus (MUS), has low and high levels of lightness in the high and middle latitudes of northern Eurasia, respectively. We examined sequence variation of the agouti signaling protein gene (Asip), which is known to be responsible for the ventral fur color. We performed phylogenetic analyses with 196 haplotype sequences of Asip (~180 kb) generated by phasing the whole-genome data of 98 wild mice reported previously. Network and phylogenetic tree construction revealed clustering of haplotypes representing the two subspecies, MUS and CAS. A number of subclusters with geographic affinities appeared within the subspecies clusters, in which the essential results were consistent with those reconstructed with whole mitochondrial genome data, indicating that the phased haplotype genome sequences of the nuclear genome can be a useful tool for tracing the dispersal of geographical lineages. The results of phylogeographic analysis showed that CAS mice with darker ventral fur possessed similar Asip haplotypes across the geographic distribution, suggesting that these haplotypes are major causes of the historical introduction of Asip haplotypes for darker ventral fur in mice from northern India to the peripheral areas, including the Japanese archipelago. Similarly, MUS in East Asia, which has a white abdomen, formed an Asip haplogroup with that from northern Iran, also with a white abdomen.

Keywords: Mus musculus; agouti signaling protein gene; inter-subspecies hybridization; nuclear genome sequence; ventral fur color variation.

MeSH terms

  • Agouti Signaling Protein* / genetics
  • Animal Fur
  • Animals
  • Genome, Mitochondrial*
  • Hair Color* / genetics
  • Haplotypes
  • Mice* / genetics
  • Phylogeny
  • Phylogeography


  • Agouti Signaling Protein
  • a protein, mouse