Dog DNA could aid quest to help breeds breathe more easily

Image credit: Kasper Flörchinger via Flickr

If you have ever taken a stroll through a popular dog park, you will have seen this classic sight. A dog owner strides purposefully ahead while their pug or french bulldog struggles to keep up, a cacophony of snorts, grunts and wheezes. These noises are part of the awkward, bumbling nature of pugs and bulldogs that attract so many to these breeds, along with their grumpy-looking, wrinkled faces. However, the noises are actually a sign that the dog is struggling to breathe.

Flat-faced dog breeds, known as brachycephalic, from the Greek words for “short” and “head”, often struggle with respiratory problems. Generations of artificial selection have resulted in dog breeds characterised by a shortened snout and protruding lower jaw. It is thought that the soft tissues in the nose, mouth and throat have not reduced in size along with the snout, and the excess tissue blocks the upper airways. Furthermore, brachycephalic breeds often have narrower nostrils than their longer-snouted counterparts, which can lead to difficulties with inhaling properly. Flat-faced dogs with these symptoms are described as having Brachycephalic Obstructive Airway Syndrome (BOAS). They suffer from breathing difficulties and are susceptible to overheating, as they cannot cool down as efficiently through panting as longer-snouted dogs.

It is thought that BOAS has a strong genetic basis, but researchers have struggled to pin it down. So far, studies have focused on the genes associated with canine skull shape variation, as these are the ones affected by selection for flatter faced dogs, but the link between these genes and the effects of BOAS are unclear. However, a condition that bears remarkable similarity to BOAS, known as upper airway syndrome (UAS), has been found in the Norwich terrier, a dog breed not considered brachycephalic. The closely related Norfolk terrier does not suffer from UAS, which suggests a recent genetic change could be responsible for the condition. Armed with this information, a group of researchers from The Roslin Institute at the University of Edinburgh aimed to determine the role of genetics in UAS, and whether these also translate to BOAS. The study was published in PLOS Genetics.

To determine which genes might be involved in upper airway syndrome in Norwich terriers, the researchers had to conduct some genetic detective work. An animal’s genome can consist of billions of letters of DNA, which code for proteins and act as a blueprint for a functioning organism. Diseases can often be caused by a single error, or mutation, in this blueprint. Attempting to find a single DNA mutation within the whole genome would be like looking for a needle in a haystack, so the team first had to identify the region of interest. To do this, they gathered DNA from two groups of Norwich terriers, one group that had severe symptoms of UAS and another that had mild to no symptoms. By comparing the DNA they could look for stretches of genetic code that were consistently different in dogs with severe UAS, which would indicate that these regions were involved.

Hopefully, this study is the first step of many in fully understanding obstructive airway syndrome and how we can treat it more effectively.

From this genetic search the researchers discovered a portion of DNA on chromosome 13 that was consistently found in severely affected dogs, which upon further inspection was found to contain the gene ADAMTS3. This gene may be important for proper drainage of waste fluid from body tissues. Studies of humans have shown that when this gene is non-functional, fluid can build up in the tissues, which results in a condition called Hennekam syndrome. Experiments on mice show similar results when the gene is fully removed, and experimenters even report mice deaths from breathing difficulties without the gene.

With the correct gene identified, the researchers sequenced the whole Norwich terrier genome, which is akin to downloading the whole blueprint for an animal. This allowed them to scour the whole ADAMTS3 gene for the error in the code that was causing breathing difficulties in these dogs. They were successful in this endeavour, and found a single DNA mutation in the gene that appeared to be responsible for upper airway syndrome in Norwich terriers. Further investigation revealed that two breeds of bulldog, which are brachycephalic, also carried the mutation, which tells us that there are other, more complex factors underpinning obstructive airway syndrome in these dogs than first realised.

The exact effect of the DNA mutation on ADAMTS3 gene function is unclear and warrants further investigation. However, the researchers suggest that based on the evidence from human and mice studies, the resultant fluid retention and swelling in the airways could put dogs at greater risk of developing the breathing problems associated with BOAS and UAS. With this knowledge, it could be possible to conduct genetic tests before birth or early in a dog’s life to determine disease risk, and take proactive measures to treat the symptoms and increase the quality of life of these dogs. Currently, BOAS is treated with corrective surgery, but this is approach is not always effective – postoperative complications and mortality are reported in many cases. Hopefully, this study is the first step of many in fully understanding obstructive airway syndrome and how we can treat it more effectively.

This post was written by Tom Edwick and edited by Miles Martin

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