Science Spin May 2008

Man's best friend, can provide insights into human disease

The dog has worked for and alongside man, as hunter, herder, guard dog, search and rescue animal, sniffer dog, guide dog and protector, ever since it was first domesticated. Furthermore, the dog is a source of unconditional affection, and is a loyal friend and companion for man. The unique relationship of dogs with humans, and their 'companion animal' status, means that the health of dogs is more closely monitored, and dog diseases are treated more intensively, than those of any other domestic animal.

For human disease researchers, it ishighly interesting that the top ten diseases in pure-bred dogs include several that also affect humans. These include cancer, epilepsy, autoimmune diseases, blindness, cataracts, and heart disease. Since dogs often share man's environment, this also means that the environmental factors that influence the development of human disease may also be involved in the development of dog diseases.

Many of the most serious human diseases, such as cancer and diabetes, arise from the expression of multiple genes, as well as environmental factors. It is very hard to pin down the genes that are disease causing as humans are very diverse, and it is hard to genetically compare one group of humans to another, and pin down the most important genes. Many breeds of dogs, however, can have long stretches of identical DNA, and that makes it easier to do comparative studies, where the disease causing genes can be identified.

Following recent advances in our understanding of the genetic make-up of dogs, this important companion animal is poised to make a major contribution to human health and welfare. Diseases in dog breeds are currently being systematically investigated, in the hope that they will provide clues to the genetic predispositions that underpin man's susceptibility to complex diseases. To understand the reasons for the growing research interest in dog diseases, we need to understand the evolutionary history of the dog.

Evolution

The dog, Canis familiaris, was domesticated from the grey wolf Canis lupus. The exact timing of this domestication is unclear. The archaeological record for dogs dates from about 15,000 years ago, but genetic studies suggest that domestication may have occurred long before that - perhaps as much as 40,000 to 135,000 years ago.

We know that dogs have been selectively bred since they were domesticated. Man has selected for all kinds of desirable features including physical appearance (such as size, shape, coat colour, and tail length) and for a range of other desirable behavioural traits (like speed, aggression, docility, and sociability). As a result of this strong selection, the modern dog population exhibits more variation in morphology (physical structure) and behaviour than any other mammalian species.

Think, for example, of the difference in size between a Chihuahua and a Great Dane.

Another consequence of this strong selective pressure has been the emergence of numerous dog 'breeds'. The derivation of dog breeds over the last few hundred years has been described as 'one of the greatest genetic experiments ever conducted by humans'.

About 350 distinct dog breeds exist today. Many of these breeds stem from a small number of founder individuals that were selected by their owners for specific features and behaviours. The progeny of these founders continue to be inter-bred. The various breeds are controlled by the Kennel Clubs and they impose strict breed standards and breeding programmes. In order to register a dog with the American Kennel Club, for example, at least both parents must have been registered in the same breed. As a result, the breeds are relatively in-bred populations and there is limited genetic diversity within each breed.

It's this inbreeding, and the resulting low levels of genetic diversity, that is the key to the use of dog breeds to track predispositions to disease. Within a breed, the DNA of individual dogs tends to be identical over very long stretches. By examining DNA from appropriate numbers of disease-affected and unaffected dogs, it should be possible to hone in on the DNA sequence differences that track with - or are 'associated with' - the disease. These types of studies are called 'whole-genome association' studies.

Humans

Heart disease, diabetes, rheumatoid arthritis, and cancer in humans are all complex diseases. Usually several genes are involved in the development of these disease and environmental factors also play an important part. Because each gene contributes only a small part to the disease process, the causes of these complex diseases have proved extremely difficult to unravel. We still do not understand how they arise, or why some people are susceptible to the disease while others do not develop the disorders.

In an effort to identify the genes that predispose to human complex diseases, whole genome association studies can be performed with DNA from human individuals. In contrast to pure-bred dogs however, human populations are extremely out-bred. Therefore, when DNA from human individuals is compared, there are far fewer- and much shorter stretches of sequence identity between any two individuals, even when the individuals are closely related. Because of all this 'noise', it is very difficult to decide which genetic differences track with health or disease in humans, and which are irrelevant in terms of disease association.

In practice, therefore, whole-genome association studies for human disease require a great deal of sequencing - with many individuals analysed and more DNA sites examined.

Genome

It has been proposed that whole genome association studies with pure-bred dogs could be a more efficient and economical way of identifying genes that predispose to complex diseases. Having identified genes that pre-dispose to complex disease in dogs, the equivalent genes could be examined in humans.

While the dog's potential to provide information about human disease has been apparent to geneticists for a long time, it is only in recent years that the molecular tools became available that would allow this potential to be realized.

Firstly the DNA sequence of a 'reference' dog was needed. A major effort to obtain this sequence got underway several years ago, and in 2005, the complete, high-quality, DNA sequence of a female boxer (Tasha) was published by researchers at the Boston-based Broad Institute.

In addition to sequencing Tasha's DNA to completion, the Broad researchers also sequenced portions of DNA from a number of individuals of several different breeds of dogs. The output from these sequencing efforts confirmed that there were long stretches of identical DNA within each breed. They also pointed out the genetic differences between breeds that the researchers had predicted. Armed with this sequence data, researchers now have the ability to do high-throughput comparisons of DNA from large numbers of dogs.