Abstract
Genetic analysis of the hair-length of Sapsaree dogs, a Korean native dog breed, showed a dominant mode of inheritance for long hair. Genome-Wide Association Study (GWAS) analysis and subsequent Mendelian segregation analysis revealed an association between OXR1, RSPO2, and PKHD1L1 on chromosome 13 (CFA13). We identified the previously reported 167 bp insertion in RSPO2 3’ untranslated region as a causative mutation for hair length variations. The analysis of 118 dog breeds and wolves revealed the selection signature on CFA13 in long-haired breeds. Haplotype analysis showed the association of only a few specific haplotypes to the breeds carrying the 167 bp insertion. The genetic diversity in the neighboring region linked to the insertion was higher in Sapsarees than in other Asian and European dog breeds carrying the same variation, suggesting an older history of its insertion in the Sapsaree genome than in that of the other breeds analyzed in this study. Our results show that the RSPO2 3’ UTR insertion is responsible for not only the furnishing phenotype but also determining the hair length of the entire body depending on the genetic background, suggesting an epistatic interaction between FGF5 and RSPO2 influencing the hair-length phenotype in dogs.
Highlights
Mammalian hair length is regulated by the activation and inhibition of the Wnt signaling pathway in the hair dermal papilla (DP) and hair matrix, which determine the hair growth cycle divided into anagen, catagen, and telogen [1–5]
The mutations in FGF5 and KRT71 were nucleotide substitutions, but the RSPO2 variant was caused by the 167 bp insertion of a 9-nucleotide (ATAATGAAC) repeat located in the 3’ UTR of RSPO2 transcripts
The logistic regression log π(x) = Xb + SNPp + Zu + e (1) 1 − π(x) was fitted: b vector containing the fixed effects associated with the traits, while gender was fitted as a fixed effect and age as a covariate; X is the design matrix containing the fixed effects related to the trait, p is the vector of the effect of Single nucleotide polymorphism (SNP) effect, u represents the vector of the random effects related to the animal effects for the trait, Z is the design matrix that corresponds to the animal effects of the trait, and e is a vector containing the residual
Summary
Mammalian hair length is regulated by the activation and inhibition of the Wnt signaling pathway in the hair dermal papilla (DP) and hair matrix, which determine the hair growth cycle divided into anagen, catagen, and telogen [1–5]. The R spondin family, including R-spondin-2 (RSPO2), has been identified to maintain the anagen phase by forming a positive feedback loop of Wnt signaling by inhibiting the Znrf3/Rnf complex that antagonizes the Wnt signaling pathway in the hair matrix [5–7]. Previous studies have identified mutations in three genes, namely FGF5, RSPO2, and keratin-71 (KRT71), to be associated with hair length, furnishing, and curl shape, respectively, in dogs [10,11]. The Sapsaree is a medium-sized, long-haired breed of dog native to Korea and frequently appears in the paintings of the Chosun dynasty, the last imperial dynasty of Korea, indicating their presence in the Korean peninsula for at least a few hundred years [16]. We showed that the hair phenotypes of Sapsarees were caused by the same mutation previously identified in the RSPO2 gene. We investigated the mode of inheritance of FGF5 and RSPO2 for hair length phenotypes in domestic dogs
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