Canine genetics key to advancing human eye disease treatment

Have you ever wondered how our close relationship with dogs extends beyond companionship to offering vital insights into human health? Night blindness, medically termed nyctalopia, is a prime example.  

This condition, which significantly hampers the ability to see in low light or darkness, can result from mutations in the RPE65 gene. Remarkably, it affects both humans and Briard dogs. This parallel in genetic conditions emphasizes the profound biological and evolutionary ties we share with our canine companions. 

The Department of Animal Breeding and Genetics at the Swedish University of Agricultural Sciences (SLU) stands at the forefront of exploring this intriguing connection. Based in the picturesque city of Uppsala, SLU's dedicated 'canine research group' comprises 30 clinicians and geneticists. They manage the Canine Biobank, housing approximately 15,000 dog DNA samples. The primary goal of this Biobank is to enhance our understanding of genetic diseases common to dogs and humans, thereby benefiting both veterinary and human medicine. But how exactly can dogs unlock new therapies for inherited eye diseases, and what implications does this have for human health? 

Tomas Bergström PhD, an Associate Professor at SLU's Department of Animal Breeding and Genetics, offers insights into this intriguing question. Bundled up against the Uppsala winter with a red scarf and black gloves, he explains, “Dogs and humans share the same environment. We eat much of the same things and we share many of the same diseases. We have such great similarities that understanding diseases in dogs makes us also understand diseases in humans, and vice-versa.”  

This concept is straightforward yet profound: identifying the genetic cause of a disease in dogs can help pinpoint the mutated genes responsible for the same inherited diseases in humans. Research has already revealed an array of diseases common to both dogs and humans, including atopic dermatitis, diabetes, epilepsy, cancer, and kidney disease.

Pinpointing mutated genes

For Bergström and his team the journey to uncovering the mysteries of inherited diseases, particularly retinal eye diseases, begins with an intricate process of DNA extraction from canine blood samples. These samples are primarily sourced from animal health clinics across Sweden.  

The laboratory's foundational work relies heavily on automated DNA extractions, a task for which they employ QIAGEN’s QIAsymphony. “The QIAsymphony is a workhorse for us when it comes to DNA and RNA extractions,” Bergström notes.  

Once the DNA has been extracted, the detective work begins: the scientists’ aim is to map each dog breed’s genes and pinpoint any mutated genes that may be causing hereditary diseases. 

Their research particularly focuses on inherited retinal eye diseases or 'retinopathies' - a group of conditions that affect the retina. This area of the eye, packed with photoreceptor cells, plays a crucial role in converting light into neural signals, which are then interpreted as images by the brain. Retinopathies, causing degenerative changes in this vital tissue, are not exclusive to humans; dogs, too, suffer from similar conditions. 

In humans, the most common forms of these disorders fall under the umbrella of retinitis pigmentosa (RP), affecting roughly 1 in 3,000 to 5,000 individuals globally. RP typically leads to a gradual loss of vision, and in many cases, can result in complete blindness. Formerly deemed untreatable, significant strides have been made in understanding and potentially treating these conditions, thanks in large part to research in canine eye diseases. 

One notable breakthrough occurred in the United States, where researchers identified the mutated gene responsible for night blindness in Briard dogs. This discovery was monumental, paving the way for gene therapy trials in humans, where the normal variant of the gene is inserted into a patient's cells to combat the same condition.

Potential benefits for human healthcare

According to Dr. Bergström, this example highlights the huge potential gains that canine gene research could have for human healthcare. 
 
“Our first goal is to identify genetic variants that cause diseases in dogs. But we also know that most of these diseases are also found in humans, so dogs are also helping us to identify genetic variants that are important for human diseases. This means that human research is really benefiting from the canine research and vice versa,” he explained. 

A prime example of this beneficial relationship was demonstrated in the work of Bergström’s group and Cathryn Mellersh’s team at the UK-based Animal Health Trust. Their research, published in 2011 and 2014, focused on progressive retinal atrophy in Golden Retriever dogs.  

They discovered two mutated genes (SLC4A3 and TTC8) responsible for the canine equivalent of retinitis pigmentosa (RP) in this breed. Intriguingly, the SLC4A3 gene had not been previously identified in human RP patients.  

The findings from the canine study opened new avenues for investigating this gene as a potential culprit in human RP cases. For Golden Retrievers, this research has enabled breeders to make more informed decisions, helping to reduce the incidence of the disease in future generations. 

These breakthroughs highlight how understanding genetic causes of hereditary diseases in dogs can illuminate similar conditions in humans, potentially leading to new treatments.

The perfect model for human disease?

But why focus on dogs? Bergström points out that dogs, from Great Danes to Chihuahuas, share more similarities with humans than most other model organisms, especially in aspects like eye structure. “The reason for using dogs as a model for human diseases really has to do with the history of dogs,” Bergström explains. 

The domestication of wolves around 15,000 to 30,000 years ago led to a 'genetic bottleneck', reducing genetic variation. This process was intensified in the mid-1800s with the establishment of dog breeding standards in Europe, further narrowing genetic diversity within each breed. These historical factors make dogs particularly suitable as models for studying genetic diseases, as they present a unique blend of genetic homogeneity within breeds and diversity across breeds, mirroring aspects of human genetic conditions. 

As a result, each breed of dog has a clearly distinguishable genetic landscape with a high degree of genetic similarity within breeds and large differences between breeds. This makes it easier to identify causal gene variations for specific illnesses.  

“Because the genetic variation is so low within dog breeds, it is faster and easier to find each individual gene responsible for a disease than it is in humans,” Bergström says. 
 
Once a disease-causing gene has been discovered and linked to a specific disease in dogs, scientists can assess whether the same gene may be of importance for similar conditions in humans. 

Bergström states, "Our first goal is to find the mutation. Our second goal is to understand what that mutation does."  

This research is crucial for both canine and human health advancements. “The real challenge for modern biology is to define what’s needed to invent therapies and pharmaceuticals for successful treatment of diseases.”