Dr. Tomas Bergström and his team are carrying out groundbreaking genetic research on dogs that has huge potential benefits for human health.
Guide dogs have been lending their sharp eyes to visually impaired and blind people for many years. And today, man’s best friend is at the forefront of pioneering research that could lead to therapies for human eye diseases and other inherited illnesses.
The Department of Animal Breeding and Genetics at the Swedish University of Agricultural Sciences (SLU) is one of the institutions leading global research into canine DNA and its implications for human health. Based in the Swedish city of Uppsala, SLU’s 30-strong ‘canine research group’ of clinicians and geneticists has its own Canine Biobank containing some 15,000 dog DNA samples. The Biobank’s purpose is to increase knowledge of the biology of genetic diseases occurring in both dogs and humans - and to use that knowledge to support both veterinary and human medicine.
But how can dogs possibly hold the keys to new therapies for inherited eye diseases in people?
Man and dog’s long shared history
Dr. Tomas Bergström is Associate Professor at SLU’s Department of Animal Breeding and Genetics, where he arrives warmly dressed for the snowy winter in a red scarf and black gloves. He says the answer to that question lies partly in the long shared history between man and his four-legged friends.
“Dogs and humans share the same environment. We eat much of the same things and we share many of the same diseases,” he says. “We have such great similarities that understanding diseases in dogs makes us also understand diseases in humans, and vice-versa.”
Simply put, identifying the genetic cause of a disease in our canine friends can help reveal which mutated genes are responsible for causing the same inherited disease in people. Scientists have so far uncovered a wide variety of diseases shared by dogs and humans, ranging from atopic dermatitis and diabetes to epilepsy, cancer and kidney disease.
For Dr. Bergström and his laboratory team, the first stage of work involves using QIAGEN’s QIAsymphony to carry out automated DNA extractions from canine blood samples, most of which are provided by animal health clinics around Sweden.
“The QIAsymphony is a workhorse for us when it comes to DNA and RNA extractions,” explains Dr. Bergström, adding that his laboratory also uses QIAGEN’s HotStarTaq Plus DNA Polymerase enzymes and the QIAGEN OneStep RT-PCR Kit for gene expression analysis.
Pinpointing mutated genes
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.
Inherited retinal eye diseases or ‘retinopathies’ are a major focus of the SLU team’s work. Retinopathies are a cluster of conditions relating to the eye’s retina, which is the area at the back of the eye with photoreceptor cells that absorb light and send a signal to the brain that is interpreted as an image.
Both dogs and people can suffer from degenerative retinal disorders. The most common such conditions in humans are collectively known as retinitis pigmentosa (RP). They affect an estimated one in 3,000 to 5,000 people worldwide who experience gradual loss of vision and possibly even blindness.
This hereditary disease was formerly considered untreatable. However, research into canine eye disease has already paved the way for clinical trial treatments.
One of the earliest successes in this field occurred in the U.S., where scientists discovered the mutated gene responsible for causing night blindness in the Briard breed of dogs. That finding eventually led to gene therapy trials – where the normal variant of the gene was inserted into a patient’s cells – for the same condition in humans.
“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.”Dr. Tomas Bergström, ASSOCIATE PROFESSOR, DEPARTMENT OF ANIMAL BREEDING AND GENETICS - SWEDISH UNIVERSITY OF AGRICULTURAL SCIENCES, UPPSALA
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.
In 2011 and 2014 the Tomas Bergström group together with Cathryn Mellersh’s team at the UK-based Animal Health Trust published their work on progressive retinal atrophy in Golden Retriever dogs. Their research revealed two mutated genes (SLC4A3 and TTC8) responsible for the canine equivalent of retinitis pigmentosa (RP) in that breed.
The SLC4A3 gene had not previously been identified in human patients with RP. But thanks to the canine research it can now be investigated as a candidate gene in other studies. For dogs, the finding has helped breeders of Golden Retrievers to plan their breeding in such a way that they can avoid the diseases.
Breakthroughs such as this one illustrate how understanding the genetic causes of hereditary diseases in dogs can help detect the cause of similar conditions in humans – and potentially lead to treatments.
But why are dogs, rather than any other animal, the subject of this research? According to Dr. Bergström, our canine friends – from Great Danes to Chihuahuas – resemble humans more than most other model organisms. For example, a dog’s eye resembles a human’s eye much more than a rodent’s.
The long-shared history between man and his four-legged friends is another contributing factor. “The reason for using dogs as a model for human diseases really has to do with the history of dogs,” Dr. Bergström explains.
Man first began domesticating wolves an estimated 15,000 to 30,000 years ago in a process that caused what’s known as a ‘genetic bottleneck’, meaning a reduction in genetic variation.
Much later, in the mid-1800s, a second genetic bottleneck was caused by the introduction of dog breeding standards in Europe. Those standards stipulated the appearance of different breeds, from Labradors to Poodles. And as a side effect, they drastically reduced the genetic variation within each particular dog breed.
Applying canine research findings to humans
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,” Dr. Bergström said.
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.
Whole-genome sequencing speeds up lab research
Back in the brightly-lit laboratory in Sweden, the pace of SLU’s research has increased exponentially in recent years thanks to the plummeting cost of whole-genome sequencing.
The team initially identified mutated genes in dogs using the traditional method of collecting 20 control samples and 20 cases, then comparing them in a laborious process of genome-wide association analysis that could take up to one year.
Today, the same stage can be reached within weeks using whole genome sequencing. This enables Dr. Bergström and his team to identify the mutated gene that is underlying a specific inherited disease much more quickly by comparing the same genes within a dog family, where the parents are healthy but the offspring suffer a disease. Once the gene mutation has been discovered in the sufferer, the hard work begins.
“Our first goal is to find the mutation. Our second goal is to understand what that mutation does. What is the biology of the disease? What protein does it interact with? Once you know that, you can start thinking about therapies,” Dr. Bergström said.
The SLU’s findings are already helping dog breeders to make educated decisions on how to choose parents for the next generation of puppies.
The new ‘Nordic Canine Genome Project’ will reveal further vital information about canine health. Launched this spring, the three-year project aims to get complete genome sequences of 100 dogs of which about 30 breeds are native to the Nordic countries of Iceland, Denmark, Norway, Finland and Sweden.
The project, sponsored by the Swedish Kennel Club and insurance company AGRIA, will shed light on which genetic variations are the norm within each dog breed – and which are likely to cause inherited diseases among those breeds.
When it comes to human health, identifying the mutated gene responsible for inherited eye diseases and other conditions in dogs is just the first step towards reducing the frequency of the mutation within the dog breed – and allowing development of effective treatments for canine and human patients.
The next step – and the most difficult one – is to identify and understand the biology of each of the mutations and exactly how they cause diseases. "In future, understanding the underlying biological processes that cause diseases will be the most important part of this work,” Dr. Bergström explains.
“The real challenge for modern biology is to define what’s needed to invent therapies and pharmaceuticals for successful treatment of diseases.”
The Department of Animal Breeding and Genetics belongs to the Faculty of Veterinary Medicine and Animal Science at the Swedish University of Agricultural Sciences (SLU) in Uppsala. The department conducts research on domestic animals in the fields of molecular genetics and bioinformatics as well as quantitative and applied genetics. Its Canine Biobank, developed in collaboration between SLU and Uppsala University, is intended to increase knowledge of the biology of genetic diseases occurring in both dogs and humans. The research aims to improve canine and human health and support veterinary and human medicine. The laboratory also offers genetic services for animals such as parental control or testing for inherited diseases. http://bit.ly/SLUGenetics