What you can’t tell by just an Instagram scroll through your favorite bulldogs is how exquisitely messed up their breed is. Behind those adorable flaps are dogs whose poor genetic diversity creates a host of health problems including, but not limited to, breathing difficulties. The root issue for French and English bulldogs has long been thought to be their squished faces, but a new study points out another factor that may be compounding the problem.
This discovery links back to a different sort of dog: The decidedly un-squished-faced Norwich Terrier. On Thursday, scientists reported in PLOS Genetics that these plucky little dogs are uniquely linked to French and English bulldogs through a DNA mutation in a gene called ADAMTS3. Not all members of these breeds have this mutation, but its existence in some is thought to result in breathing issues.
Lead author Jeffrey Schoenebeck, Ph.D., a research fellow at the University of Edinburgh’s Roslin Institute tells Inverse that clinical researchers have known for a while that the skull shape of short-faced dogs like bulldogs and pugs is a major risk factor for airway obstruction — a condition called Brachycephalic Obstructive Airway Syndrome (BOAS).
In the 1990s, veterinarians began to realize that Norwich Terriers were also coming down with an obstructive airway problem. But back then, veterinarians thought that because the breeds are so different the problem must be different as well. Their condition was labelled Upper Airway Syndrome.
“Fast-forward to the genetic revolution in dogs, and we now have more capabilities to map diseases in dogs,” Schoenebeck says. “We began to look at what are the genetics of this disease in Norwich Terriers, and that led us to the discovery.”
To get there, the team analyzed the genes of 233 Norwich Terriers and looked for an association between their genomes and respiratory disease severity. This revealed that dogs with breathing problems shared a DNA mutation.
As a followup, the team then screened over 100 breeds looking for the ADAMTS3 variant and found that it seems to only exist in three: the Norwich Terrier, the English bulldog, and the French bulldog. It’s still unknown why only these three dogs have the variant.
“Why would it be that out of all the breeds we screened — and we screened many — we find it in these three breeds?” Schoenebeck asks. “That’s a pretty vexing question for me.”
He hypothesizes that perhaps, way back in history, there was an ancestor who gave rise to these three breeds. But, more realistically and recently, it probably has to do with breeders choosing specific traits, and those are related in some way to the mutation.
How exactly breeders should react to this information is a bit of an unknown as well. When it comes to Norwich Terriers, the team knows that having two copies of the mutation is very strongly associated with the likelihood of developing severe breathing problems. For these dogs, they feel confident in advising breeders to use genetic testing as a means to screen their dogs and decide how to breed them.
But because skull shape also affects how well English and French bulldogs breathe, the scientists are uncertain about the extent to which the gene mutation drives the issue. There’s also the issue of accidentally promoting even worse genetic diversity: In this study, 85 percent of the English bulldogs examined carried the mutation. If these dogs weren’t used in future breedings, that would leave an even smaller pool of dogs.
“If breeders began to select among those 15 percent of dogs that don’t have the mutation, that could increase the amount of inbreeding, which could cause even more problems for the breed and outweigh the risks that this mutation presents,” Schoenebeck explains.
The goal of the researchers is to provide advice that can help protect the health of the animals. But when an animal is already predisposed to ill health, it becomes a trickier situation.
In flat-faced dog breeds, air resistance caused by skull conformation is believed to be a major determinant of Brachycephalic Obstructive Airway Syndrome (BOAS). The clinical presentation of BOAS is heterogeneous, suggesting determinants independent of skull conformation contribute to airway disease. Norwich Terriers, a mesocephalic breed, are predisposed to Upper Airway Syndrome (UAS), a disease whose pathological features overlap with BOAS. Our health screening clinic examined and scored the airways of 401 Norwich Terriers by laryngoscopy. Genome-wide association analyses of UAS-related pathologies revealed a genetic association on canine chromosome 13 (rs9043975, p = 7.79x10-16). Whole genome resequencing was used to identify causal variant(s) within a 414 kb critical interval. This approach highlighted an error in the CanFam3.1 dog assembly, which when resolved, led to the discovery of a c.2786G>A missense variant in exon 20 of the positional candidate gene, ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). In addition to segregating with UAS amongst Norwich Terriers, the ADAMTS3 c.2786G>A risk allele frequency was enriched among the BOAS-susceptible French and (English) Bulldogs. Previous studies indicate that ADAMTS3 loss of function results in lymphoedema. Our results suggest a new paradigm in the understanding of canine upper airway disease aetiology: airway oedema caused by disruption of ADAMTS3 predisposes dogs to respiratory obstruction. These findings will enhance breeding practices and could refine the prognostics of surgical interventions that are often used to treat airway obstruction.