Doggy DNA banks could stop the UK’s rarest breeds going extinct

With only 53 registrations last year, the Skye Terrier is one of the rarest dog breeds in the UK, and a liver disease is putting it even more at threat. But doggy DNA tests could save the day
Getty Images / WIRED

With its trademark fringe and pavement-sweeping long coat, the Skye Terrier is about as recognisable a pooch as they come. But the fluffy breed – perhaps most famous for serving as the inspiration for Dougal in the 1960s children’s TV show The Magic Roundabout – is facing a grave threat.

The Skye Terrier is on the verge of disappearing altogether. In 2004, The Kennel Club put the dog on its list of vulnerable breeds, which charts all dog breeds with fewer than 300 registrations in the UK each year. Last year, just 53 new Skye Terriers were registered in the UK – only the Sussex Spaniel, the Otterhound, and the Irish Red & White Setter are more imperilled.

This shrinking gene pool piles more danger onto the Skye’s already-precarious position. The breed is prone to a fatal, hereditary form of hepatitis, and the smaller the breeding population, the harder it is to find dogs without the disease to breed. But there is a glimmer of salvation on the horizon: DNA tests.

In 2006, the Skye Terrier Club, a group of breeders, enthusiasts, and owners, decided to use its network to solicit swab samples of the dog to build a DNA bank for the breed. Originally investigating a kidney disease the dogs are predisposed to, the organisation raised enough money to have the affliction studied by veterinary scientists at Cambridge University, and geneticists at the Animal Health Trust.

But it quickly emerged that a strain of hepatitis that some breed enthusiasts had erroneously thought was no longer an issue was the most pressing concern. An out-of-the-ordinary copper accumulation was first linked to the Skyes' chronic hepatitis in 1988. The cases were few and far between, but, in 2012, with the DNA collection in full swing, they began to grow again and veterinary scientists at Cambridge confirmed the illness was the same as that studied in the 80s.

As the Skye terrier has declined in popularity – crowded out by more fashionable breeds like pugs and cockapoos – the problem has become more pronounced. Today, the Club estimates there are only 5,000 Skyes in the world. To put that into context, over 40,000 new Labradors are registered in the UK yearly. "It's a truly very, very, small number," says Maud Hawkes, chair of the Skye Terrier Club Health Committee.

While the Skyes aren't dying en masse just yet, that the mutation is present in such a small population means that it's an existential risk on the horizon for the breed. With each generation of puppies, only about ten per cent of these are used for breeding, so 90 per cent of the genetic material carried by the dogs is lost. The smaller that gene pool becomes, the higher the chances that two dogs carrying the strain will be mated together. There's little data on the prevalence of the liver disease as yet, although the Club hopes access to an eventual DNA testing kit will turn up more information.

"Once a breed becomes low in numbers it becomes unsustainable because you have a limited population to breed from," says Bill Lambert from the Kennel Club, which currently offers health test packages for 20 breeds. "You're then forced to breed close siblings, which is obviously not a good idea."

Like many of the chronic conditions affecting dogs, the Skye’s hepatitis-causing gene mutation emerged because of in-breeding. In the past, the same 'champion' dogs would be mated over and over again, but now there's greater understanding in the breeding community that this level of inbreeding leads to serious genetic risk. The conundrum is that maintaining the characteristics of a pedigree with a small population necessitates a certain degree of inbreeding, and this leads to increased risk of recessive diseases. The positive outcomes of dog breeding, like the appearances that make them unique, can never be entirely separated from the negative.

Before testing was available, trying to pick un-afflicted dogs was basically guesswork. There are some measures breeders can take to help their chances. Guide Dogs UK, for example, restricts the litter output of a single dog, and to ensure mating pairs are as unrelated as possible, uses a statistical model first put together by evolutionary geneticist Sewall Wright, the Coefficient of Inbreeding, which calculates hereditary risk by analysing the family trees of dogs before they're mated. Other breeds opt for a kind of canine internationalism that takes advantage of natural distance to avoid breeding dogs together with too close a lineage.

This is a tactic used by the Skye Terrier Club. Health committee chair Hawkes has three very cosmopolitan Skyes: Banquo, whose father is Danish, but whose grandfather was bred in the USA; Poika's dad was Finnish, his mum a pure Scottish-bred, and Beda is half-Czech, half-German. The Skye Terrier Club communicates with chapters of Skye enthusiasts from Finland to Australia and America, and imports are now encouraged by the Kennel Club with something called a 'pet passport'.

Cheaper genetic testing also means that it’s easier to select suitable dogs within a certain geography. The Animal Health Trust's Cathryn Mellersh says that in the past researchers would have had to make a guess at the gene responsible, then take DNA from an affected dog and sequence that guess, a lengthy six-month process. If there wasn't a difference between the two genetic codes, you'd repeat the process with your next-best guess.

But advances in genetic technologies that became affordable roughly five years ago mean the whole strand of doggy DNA can now be mapped. Using whole genome sequencing the Animal Health Trust and Cambridge University hope to isolate the hepatitis mutation by comparing variants in genetic code between two of the sick Skyes, volunteered by the community, and healthy dogs. In doing so, they plan to develop a simple swab or blood test – so that breeders can identify canines carrying the mutation, limit the spread to new litters, and slowly but surely eradicate the mutation from the population.

To find the offending gene, the AHT and Cambridge are using whole genome wide association studies to comb the 2.4 billion letters of DNA in the dog genome, 30,000 different genes, and the average of 6 million differences between any two dogs. For the Skye Terrier, the researchers are searching for a 'simple' genetic condition - meaning that the hepatitis is defined by a single gene.

Most hereditary illnesses, though, are complex conditions, which occur when there are multiple risk factors at play, usually at least two genes, and environmental factors as in the auto-immune disease that affects the Nova Scotia duck tolling retriever.

"So that's what we've been doing," says Mellersh, "building up a genome bank of dog sequences. What that means is you can take your Skye that has the disease, and compare his or her genome with others who don't have the liver disease. What you hope is that you find the one place where a Skye Terrier's DNA differs."

Mellersh says that if you took all the DNA in the dog, and each letter was a millimetre long, it'd stretch from Land's End to John O'Groats and back again. "We've narrowed the search to a couple of kilometres," Mellersh adds. "We're not exactly sure which letter of DNA it is yet, but we've excluded a lot of the genome – we're getting closer."

The research won't just benefit the Skye Terrier. For example, if geneticists were next to investigate an eye disease among Labradors, the sequenced terrier could serve as a 'control' dog while the Labrador with the gammy eye is the 'case'. The more dogs sequenced, the better.

Shortly after the turn of the millennium, a boxer called Tasha had her genome sequenced (view her here on Ensembl). It became common practice to sequence dogs and compare them to Tasha, the reference, but having an archive of controls makes the technique more powerful. By building the number of reference genomes available, the number of variants in sick dogs becomes smaller and more manageable to look through.

That's one reason why Tosso Leeb at the University of Bern founded the Dog Biomedical Variant Data Consortium (DBVDC), a worldwide effort to compile DNA data across breeds into a single library. Today, the group has 590 canine genomes on its books, ranging from the Australian Cattle Dog to the Basenji hound, the Tibetan Terrier, and the Berger Picard.

Whole genome sequencing has already led to successes: in 2018, research led by professor Hannes Lohi at the University of Helsinki, also a participant in the DBVDC, identified a new gene for canine congenital eye disease. And last year, researchers discovered the gene variant that underlies curly fur in the KRT71 keratin gene, a morphological trait that also has implications for explaining hair growth disturbances and baldness.

The Helsinki DNA bank opened in 2006 and is one of the largest in the world – more than 80,000 DNA samples from 330 breeds of dogs, filling about 25 freezers in its lab, plus 10,000 tissue samples from other organs. It invites dog owners to participate, promoting ongoing studies in social media, breed clubs, and vet clinics.

"Over the past 15 years, we have built an extensive network of collaboration with the canine world in all its levels," Lohi says. "This is a real citizen science approach. Without the owners and their willingness to participate we would not have many samples."

Unfortunately for the Skye Terrier, the Covid-19 crisis has forced the Animal Health Trust to close its doors. Although the 78-year-old charity has permanently shut now, the breeds' DNA samples and records are in safe storage, and Mellersh hopes to relocate to Cambridge University where the search can resume. "I was more pessimistic for the breed about a decade ago," says Hawkes. "But, actually, I think it is moving forward."

This article was originally published by WIRED UK