Identifying genetic disorders in dogs

The genes responsible for some serious genetic conditions in dogs have now been identified using a new technique, using a very small number of animals. The new method relies on the exceptional similarity in the genetic code of dogs of the same breed.

> Dogs and genetics

> Identifying ridgeback genes

> Identifying genetic disorders

> Canine leukocyte adhesion deficiency

> Stationary night blindness

> References

Dogs and genetics

Dogs have been bred selectively for particular traits ever since humans first tamed grey wolves between 15,000 and 100,000 years ago. There are over 400 breeds of dog today, and these are descended from only a handful of canine ancestors. This breeding history is unique, and means dogs of a single breed have long stretches of identical genetic code. Their genetic similarity can be greater than that seen in laboratory rodents, which are inbred specifically to keep their genetic code similar.

In genetics it is important that all the animals studied are as similar as possible. This makes it easier to spot any changes that occur. A team at The Broad Institute of Harvard and Massachusetts Institute of technology have found that it is possible to identify the genes responsible for specific genetic diseases in dogs, using as few as 10 animals with the condition and 10 without.

Identifying ridgeback genes

A gene-chip was used to analyse thousands of single-base differences across the whole genome in the Rhodesian ridgeback. They found a region of 750,000 base-pairs which differed between dogs which had the breed’s characteristic ridge on their back and those which lacked it. Only 5% of Ridgebacks do not have the ridge, because breeders select for it. These dogs were compared with Thai Ridgebacks, which are only distantly related to Rhodesians, but which also have the ridgeback trait. By comparing the same stretch of DNA between the two breeds the genes responsible for the trait were found. Four genes involved in development of the foetus are duplicated in dogs with the ridgeback trait.1

Identifying genetic disorders

Particular genetic diseases and defects are often associated with the selective breeding in dogs, and almost one-tenth of Rhodesian ridgebacks suffer from dermoid sinus. In this developmental disorder the skin fails to separate from the nerve chord. It is a painful condition and the animals are usually put down. 

The study found that animals which had a duplication of the four genes were ridged, but those which had two duplicate copies of the genes had an 80% risk of dermoid sinus.2 This technology will be used in further studies to identify other genes responsible for genetic disorders, including those which effect both dogs and other species.

Canine leukocyte adhesion deficiency

This rare, but devastating, disease causes Irish setter puppies to die from multiple serious infections that cannot be warded off with antibiotics. Canine LAD bears many similarities to human LAD and bovine LAD. From previous research on these diseases it was known that it is caused by having two copies of a mutation on the beta-2 integrin gene3. Once this was confirmed to be the case in the dogs, a genetic test was developed to screen large populations4. The tests revealed that approximately 12% of Irish red setters in England and Scandinavia were carriers of this gene5. By ensuring that two carriers never mate the disease is now non-existent and the genetic mutation could be eradicated within a couple of generations.

Stationary night blindness

The large French sheep dogs Briards are affected by an inherited eye disorder called stationary night blindness. In some dogs it has been possible to restore their sight by injecting copies of a normal gene directly into the retina6. It was the genetic similarities between all mammals that made this possible - the gene responsible for the night blindness in Briards, RPE65, was first identified in mice and people. Now this gene therapy treatment is being trialled in human patients with the similar disease Leber congenital amaurosis7.

References

1. Karlsson, E et al (2007) Efficient mapping of mendelian traits in dogs through genome-wide association Nature Genetics 39, 1321 - 1328

2. Hillbertz, N et al (2007) Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs Nature Genetics 39, 1318 - 1320

3. Kijas, JM et al (1999) A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency Genomics 61(1):101-7 http://www.ncbi.nlm.nih.gov/pubmed/10512685

4. Kijas, JM et al (2000) Detection of the causal mutation for canine leukocyte adhesion deficiency (CLAD) using pyrosequencing Anim Genet. 31(5):326-8 http://www.ncbi.nlm.nih.gov/pubmed/11105214

5. http://www.optigen.com/opt9_test_clad.html

6. http://www.akcchf.org/research/success-stories/giving-eyesight-to-the-blind.html

7. Stein, L et al (2011) Clinical gene therapy for the treatment of RPE65-associated Leber congenital amaurosis Expert Opin Biol Ther. 11(3):429-39 doi:10.1517/14712598.2011.557358