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

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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.

No MeSH data available.


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.
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f3: 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.

Mentions: There were 144 annotated genes in the mapping interval linked with the kinked/short-tailed trait, 11 of which are involved in skeleton development of mice (Table S3). To identify the causal mutation(s), we screened genetic variations, including both SNPs and indels, within the candidate genes on the basis of the whole genome resequencing data of the cat pedigree. While no indel was detected from the coding region of the candidate genes, 2,907 SNPs were identified, of which 68 matched the dominant inheritance model of kinked tails in the pedigree, and were further analyzed. Twelve of the 68 SNPs were non-synonymous substitutions, within which only two (c.2969G > C of ZBTB4 and c.5T > C of HES7) caused amino acid changes at evolutionary conserved residue sites, and were considered as the likely mutations (Table S4). Both candidate variants were tested in 16 kinked-tailed and 16 normal-tailed cats. ZBTB4 c.2969G > C was not associated with kinked tails (p = 0.600) and excluded, whereas HES7 c.5T > C showed strong signal of association with the kinked-tailed trait (p = 3.33E-9), considered as the causal mutation. HES7 encodes a basic helix-loop-helix oscillatory transcriptional repressor regulating somite segmentation through the Notch pathway212223. Mutations in HES7 have been shown to be associated with spondylocostal dysostosis (SCD), an axial skeleton development disorder characterized by extensive hemivertebrae and rib anomalies in humans and dogs2425262728, and HES7-knockout mice exhibit kinked tail in addition to malformation in the spine and ribs2328. The c.5T > C causes a valine-to-alanine missense substitution (p.V2A) at an evolutionarily conserved amino acid residue site in the HES7 protein (Fig. 3). Predictions of the effects of amino acid substitution on protein function by SIFT2930 and PolyPhen31 suggested that p.V2A may be deleterious to the HES7 protein. Therefore, c.5T > C in HES7 is probably the causal mutation responsible for the kinked/short tails in Asian domestic cats.


Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats
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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997960&req=5

f3: 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.
Mentions: There were 144 annotated genes in the mapping interval linked with the kinked/short-tailed trait, 11 of which are involved in skeleton development of mice (Table S3). To identify the causal mutation(s), we screened genetic variations, including both SNPs and indels, within the candidate genes on the basis of the whole genome resequencing data of the cat pedigree. While no indel was detected from the coding region of the candidate genes, 2,907 SNPs were identified, of which 68 matched the dominant inheritance model of kinked tails in the pedigree, and were further analyzed. Twelve of the 68 SNPs were non-synonymous substitutions, within which only two (c.2969G > C of ZBTB4 and c.5T > C of HES7) caused amino acid changes at evolutionary conserved residue sites, and were considered as the likely mutations (Table S4). Both candidate variants were tested in 16 kinked-tailed and 16 normal-tailed cats. ZBTB4 c.2969G > C was not associated with kinked tails (p = 0.600) and excluded, whereas HES7 c.5T > C showed strong signal of association with the kinked-tailed trait (p = 3.33E-9), considered as the causal mutation. HES7 encodes a basic helix-loop-helix oscillatory transcriptional repressor regulating somite segmentation through the Notch pathway212223. Mutations in HES7 have been shown to be associated with spondylocostal dysostosis (SCD), an axial skeleton development disorder characterized by extensive hemivertebrae and rib anomalies in humans and dogs2425262728, and HES7-knockout mice exhibit kinked tail in addition to malformation in the spine and ribs2328. The c.5T > C causes a valine-to-alanine missense substitution (p.V2A) at an evolutionarily conserved amino acid residue site in the HES7 protein (Fig. 3). Predictions of the effects of amino acid substitution on protein function by SIFT2930 and PolyPhen31 suggested that p.V2A may be deleterious to the HES7 protein. Therefore, c.5T > C in HES7 is probably the causal mutation responsible for the kinked/short tails in Asian domestic cats.

View Article: PubMed Central - PubMed

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.

No MeSH data available.