Abstract
Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10−37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.
Highlights
Morphological differences have been one of the primary drivers of dog breed formation since wolf domestication and subsequent selection to create dog breeds [1]
One group of three breeds (Bulldog, French Bulldog and Boston Terrier) is characterized by a wide head, short muzzle, widely spaced eyes, small size and abnormalities of the vertebral bones of the back and tail. These breeds are referred to as the screw tail breeds since the characteristic that is unique and easy to see in these breeds is their shortened and kinked tails. These breed have become increasingly popular as pet dogs, they have health issues associated with their morphology
The mutation and the affected gene identified are very similar to the types of mutations that have been shown to be responsible for a rare human disorder with similar clinical abnormalities, called Robinow syndrome
Summary
Morphological differences have been one of the primary drivers of dog breed formation since wolf domestication and subsequent selection to create dog breeds [1]. Some subsets of dog breeds share distinctive morphologies. A shortened and kinked tail— which is referred to as a “screw tail”—is one of the distinctive morphological traits that characterizes Bulldogs, French Bulldogs and Boston Terriers, which were historically developed from the Bulldog breed and, closely related [7]. These breeds share a craniofacial morphological phenotype referred to as brachycephaly, which includes both profound shortening of the muzzle and widening of the skull. In addition to morphological features, certain diseases are found at a high prevalence across all 3 breeds such as vertebral malformations [9,10,11,12,13], cleft lip and cleft palate [14,15,16], congenital heart disease [17, 18, 19], and glioma [5, 20, 21]
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