Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds

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.

Congenital malformations of the lumbosacral vertebral column are common in neurologically normal French Bulldogs, English Bulldogs, and Pugs, with breed‐specific differences

“…This is in agreement with the breed‐specific differences demonstrated in this and additionally in previous studies . In summary our results agree with the suggestion that Pugs should therefore not be considered a “screw‐tailed” brachycephalic breed like French and English Bulldogs …”

“…On the contrary the smooth curvature of the less extreme tail phenotype in Pugs has been hypothesized to be caused by vertebra curva that is caused by asymmetric tension of the soft tissue structures of the tail rather than by true congenital vertebral malformations . A recent study identified a mutation in the gene DVL2 in English Bulldogs, French Bulldogs, and Boston Terriers but not in Pugs that is linked with thoracic and coccygeal vertebral column malformations in a recessive manner . This is in agreement with the breed‐specific differences demonstrated in this and additionally in previous studies .…”

“…While the cause and pathogenesis of these malformations remain unknown, most studies support multifactorial etiologies . A recent study has identified a mutation in the gene DVL2 linked with thoracic and caudal vertebral column malformations in English Bulldogs, French Bulldogs, and Boston Terriers but not in Pugs . In French bulldogs, an association has been shown to exist between the degree of tail malformation and the severity of thoracic hemivertebrae and it has been suggested that the selection of dogs with a “screw‐tailed” phenotype for breeding will cause a further increase in the prevalence of hemivertebrae …”

Skin and ear health in a group of English bulldogs in Finland – a descriptive study with special reference to owner perceptions

“…EB as a breed has low genetic diversity, which may be an obstacle to recreating healthier phenotypes from the existing genetic pool . Moreover, in one study a frameshift mutation in the gene DISHEVELLED 2 ( DVL2 ) was found in EBs and other breeds that share many similar morphological and disease‐predisposition traits such as a brachycephalic skull morphology and vertebral malformations . Analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations to those exhibited in EBs.…”

“…30 Moreover, in one study a frameshift mutation in the gene DISHEVELLED 2 (DVL2) was found in EBs and other breeds that share many similar morphological and disease-predisposition traits such as a brachycephalic skull morphology and vertebral malformations. 31 Analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations to those exhibited in EBs. If the breed-associated characteristics are linked to a gene causing congenital disorders, it should be questioned why a characteristic that should be regarded as "abnormal" has actually become "normal" or even desired in the breed, and whether a better health status could be achievable with cross-breeding.…”