Identification of a genetic locus responsible for the dominant white-spotting coat phenotype in mice spontaneously isolated from a Japanese wild-derived inbred strain

Abstract

Agouti-dominant spotting (Ads) is a novel mutant mouse that was spontaneously isolated from KOR1/Stm (KOR1), an inbred strain derived from a Japanese wild mouse. Heterozygous Ads mice exhibit dominant white-spotting on the dorsal coat, whereas homozygous mice display embryonic lethality. We generated [Ads×C57BL/6J (B6)]F₁ (F₁), F₂ and [B6×(Ads×B6)]N₂ (N₂) mice to investigate the inheritance patterns of the Ads phenotype. The segregation ratio did not conform to the theoretical values expected for a simple autosomal dominant inheritance pattern with recessive embryonic lethality, as there was a reduced number of individuals exhibiting white-spotting in F₂ (χ²=29.07, P<0.0001) and N₂ (χ²=5.79, P=0.016). Genome-wide linkage analysis revealed that the Ads locus was located within the interval between D4Mit288 (56.8-Mb) and D4Mit69 (136.1-Mb) on chromosome 4. Further fine mapping using additional N₂ and N₃ progeny and markers narrowed the Ads locus to the genomic interval between Dhcr24 (106.4-Mb) and D4Mit199 (111.7-Mb). Among the genes encoded within this genomic interval, we predicted that the mago homolog, exon junction complex core component (Magoh), was the most promising candidate gene for Ads, as its null mutations have been reported to cause a white-spotting phenotype in Mos2 mice. However, no mutations were identified in the coding region of Magoh in Ads mice, suggesting that the causative mutation for the white-spotting phenotype may reside in a cis-regulatory region of Magoh or in another novel gene within the interval.