An international team of scientists has identified the genes behind two traits in dogs: white coat colour and the ridge of raised hair along the spine of certain ‘ridgeback’ breeds. The tools
used to find the genes could speed up the discovery of genes linked to diseases in dogs, many of which also affect humans.

The work, which was partly funded by the EU, is published online in two articles in the journal Nature Genetics.

‘Dogs are a unique species, domesticated and bred by humans, who selected for traits like shape, size, colour and personality,’ said Kerstin Lindblad-Toh of the Broad Institute in the US and
Uppsala University in Sweden. ‘In addition to conserving desired traits, the selective breeding of dogs may make rare disease mutations common in a breed.’

Both of the traits under investigation are linked with medical problems; white dogs are prone to hearing loss, while many ridgeback dogs suffer from a neural tube defect called dermoid sinus.

Pedigree dogs are particularly well suited to these kinds of studies. Dogs of the same breed share long stretches of DNA, while shorter stretches are common among dogs of different breeds.

‘Our new mapping methods take advantage of the power of reduced genetic diversity in dog breeds and the sharing of mutations across breeds to identify disease genes,’ explained Elinor Karlsson
of the Broad Institute. ‘We use a two-stage approach to first find the approximate neighbourhood of the causative mutation, and then we zoom in on its specific location on the genome.’

White coat colour and the ridged back both show a simple pattern of inheritance, involving just one gene or genomic region, making them ideal for testing the two-stage strategy.

They found that the ridgeback trait is caused when the dogs have multiple copies of a region of the genome containing genes for the fibroblast growth factor (FGF). The FGF genes play an
important role in development, and the mutation leads to a defect in the planar cell polarity system. This system is needed for both the normal orientation of hair follicles and for neural-tube
closure, the scientists explain.

The research could also point the way towards eliminating the problem of dermoid sinus in the breed. The ridgeback mutation is dominant, which means that the dog only needs one copy of it to
have the characteristic ridge. The scientists found that dogs who have two copies of the mutation are more prone to dermoid sinus than dogs who have one copy of the mutation.

Currently dogs without a ridge are barred from breeding by the ridgeback breed clubs. This means that most ridgebacks have two copies of the mutation, whereas in fact the best option would be
to inherit one copy of the mutation and one normal gene. This would generate a ridge but reduce the likelihood of developing dermoid sinus.

‘The problem with dermoid sinus could be virtually eliminated by allowing ridgeless dogs in breeding and by avoiding matings between ridged dogs,’ the scientists suggest.

The scientists were also successful in pinning down the cause of the white coat to a gene called MITF, which has been implicated in both pigment and auditory disorders in humans and mice.

EU funding for the work came from the MolTools (Advanced Molecular Tools for Array-based Analyses of Genomes) project, which is financed under the ‘Life sciences, genomics and biotechnology for
health’ thematic area of the Sixth Framework Programme (FP6).

The next step for the researchers is to apply their tools to more complex diseases, such as cancers and autoimmune disease, which have many genetic and environmental causes. Because of the
unique genome of purebred dogs, the scientists only need to test the DNA of a few hundred individuals to pin down the genes involved, compared to the thousands of subjects that are required to
study these diseases in humans.

Professor Lindblad-Toh won one of the 2007 EURYI awards to continue her work in this field at Uppsala University.

‘We will look at different diseases and also different behaviour, but our main focus is on cancer,’ she said on winning the award. ‘At present we are looking at cancer in the blood vessel where
we have found very exciting genes, and I am very hopeful. Once we have identified canine disease genes we will collaborate with clinicians and human geneticists to study if the same genes are
significant for the disease in human patients.’

For more information, please visit:
http://www.nature.com/naturegenetics

Dog disease research at Uppsala University:
http://www.imbim.uu.se/forskning/lindbladtohresearch.html

Dog disease research at Broad Institute:
http://www.broad.mit.edu/mammals/dog/donate.html