Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats

Abstract

Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.

Figure 1. Tail phenotypes of domestic cats from Asia.

(A) a short/kinked-tailed cat in the “minor kink” category; (B) a short/kinked-tailed cat in the “medium kink” category; (C) a short/kinked-tailed cat in the “extreme kink” category; (D) a cat with a normal wild-type tail.

Figure 2. Linkage mapping of the kinked/short-tailed trait in Asian domestic cats.

(A) a two-generation cat pedigree segregating for the kinked/short-tailed trait. Squares represent males, circles represent females, and a diamond represents the stillborn kitten. Solid icons represent kinked/short-tailed cats and open icons represent normal-tailed cats. Corresponding genotypes are given under the icon of each cat. (B) Manhattan plot summarizing the results of linkage analysis of the kinked/short-tailed trait on the basis of whole genome sequencing data from the 13 cats of the pedigree. SNPs within a 100 Kb window are clustered within one column.

Figure 3. Alignment of amino acid sequences of HES7 among mammals.

Dots represent residues identical to the reference sequence of a domestic cat with a wild-type tail phenotype and dashes represent residue gaps in the alignment. The basic domain, the helix-loop-helix domain, the orange domain, and the WRPW motif are marked by green, yellow, orange and blue respectively. The amino acid residue where p.V2A is located is shaded in red.