Biomedicine

Dog DNA May Lead to Cures

The canine genome could help researchers understand such major conditions as blindness, cancer, and OCD.

In 2003, researchers using gene-sequencing machines completed a draft of the human genome, a readout of the entire sequence of nucleotides in human DNA. Now, a group of scientists from the Broad Institute of MIT and Harvard has created the first full genome sequence of a dog (a boxer named Tasha).

The researchers reported this week that they’ve also completed less-detailed genome maps of nine other breeds of domestic dogs, four types of wolves, and the California coyote. This catalogue of canine DNA will allow scientists to pinpoint the genetic differences between types of dogs and, hopefully, isolate the genes that make some dogs prone to cancer and other diseases shared with humans, as well as genes that distinguish, say, a Dachshund from a Great Dane.

“The hundreds of years of careful inbreeding to produce the various breeds have delivered a geneticist’s dream model for human genetic disease,” says Hans Ellegren, an evolutionary biologist at Uppsala University in Sweden who has followed the work.

Scientists searched the dogs’ genomes for single nucleotide polymorphisms or SNPs, locations in the genome where the exact sequence of nucleotides (the basic elements of DNA) may differ between individuals. SNPs are inherited in chunks, known as haplotypes. Scientists found that haplotypes within dog breeds are very long – about a million base pairs of DNA – compared with an average human haplotype of just 25,000 base pairs.

These long haplotypes, which reflect the high levels of genetic similarity within breeds, make looking for a disease gene more like searching for a pick-axe in haystack rather than a needle. “It’s 50,000 times easier to find these genes in dogs than in humans,” says Elinor Karlsson, a graduate student at Boston University and the Broad Institute, who analyzed dog genomes for the project.

To search for a gene involved in, say, bone cancer, scientists first compared genomes of dogs within a breed, looking for haplotypes unique to the animals that have cancer. Cancer-afflicted dogs of other breeds would likely carry similar patterns of SNPs, but in different arrangements on their chromosomes, which would help scientists to narrow down the location of the cancer-associated gene on the chromosome.

The research, published in the December 8 issue of Nature, was presented at the Bay Colony Cluster Dog Show in Boston, where scientists were collecting DNA samples from competing pooches to use in future analyses. A rough sketch of the poodle genome was published in 2003. But according to Eric Lander, director of the Broad Institute and senior author on the paper, the new sequence is stitched together far more closely than previous canine sequences, and is freely available to any researcher who wants to download it. Lander says he expects to see canine DNA microarrays – gene chips used to study how different genes interact with each other – similar to those created with human DNA, available within the next year or two.

The findings should shed light on diseases that afflict both dogs and humans, because many dog breeds suffer from genetic diseases also seen in humans, such as blindness and autoimmune disease. Because dog diseases tend to cluster in certain breeds (hip dysplasia in Golden Retrievers, for example) there’s a better chance of finding the genes linked to these differences, says Ellegren.

Claire Wade, a geneticist at Massachusetts General Hospital in Boston and an author on the paper, is comparing genomes of Greyhounds and Rottweilers, two breeds susceptible to bone cancer, to hunt down the relevant disease genes. Her group eventually plans to search for genes involved in breast cancer, diabetes, and epilepsy. Scientists could also look for genes involved in psychiatric problems, such as obsessive-compulsive disorder, which afflicts some dogs and is treated with the same drugs used to treat humans.

The high-quality of their genomes puts dogs into the top tier of sequenced mammals, along with mice and humans. Furthermore, dogs have some distinct advantages over mice as organisms for studying human diseases: they live longer than mice and they share a lifestyle, and lifestyle-related diseases, with humans. “Not only do they share regions of our DNA, they share our sofas, our snacks, and our homes, predisposing them to [diseases] such as cancer and diabetes,” says Wade.

Scientists will also use the gene catalogue to uncover the genetic basis of behavior, such as why collies herd and pointers point and why some dogs are prone to aggression. These clearly inherited behaviors were one of the reasons scientists were originally drawn to canine genetics, says Elaine Ostrander of the National Human Genome Research Institute. “Now we have the tools to really study this,” she says.

The findings also give insight into the history of dog breeding. Scientists found that all domestic dogs are derived from the grey wolf, as was expected. But researchers also found evidence that many dogs alive today are probably descended from small founding populations that lived as recently as 50 to 200 years ago, suggesting that many dog breeds as we know them today emerged only recently. “So while there are dogs that look like modern breeds in, say, Dutch paintings from the 1600s, those dogs are probably not that genetically similar to today’s breeds,” says Wade.

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