In work that sheds light on both the genetic similarities between dogs and humans and the genetic differences between dog breeds, an international research team led by scientists at the Broad Institute of MIT and Harvard announced today the completion of a high-quality genome sequence of the domestic dog.
The research will be published in the Dec. 8 issue of Nature.
Comparing dog and human DNA reveals key secrets about the regulation of the master genes that control embryonic development. Comparing dog breeds reveals the structure of genetic variation within the species. The researchers' catalog of 2.5 million specific genetic differences across several breeds can now be used to unlock the basis of physical and behavioral differences, as well to find the genetic underpinnings of diseases common to domestic dogs and their human companions.
"The incredible physical and behavioral diversity of dogs -- from Chihuahuas to Great Danes -- is encoded in their genomes," said senior author Eric Lander, director of the Broad Institute and a professor of biology at MIT. The sequencing of that genome "can uniquely help us understand embryonic development, neurobiology, human disease and the basis of evolution," said Lander, who is also a professor of systems biology at Harvard Medical School and a member of the Whitehead Institute for Biomedical Research.
Dogs not only occupy a special place in human hearts, they also sit at a key branch point in the evolutionary tree relative to humans. By tracking evolution's genetic footprints through the dog, human and mouse genomes, the scientists found that humans share more of their ancestral DNA with dogs than with mice, confirming the utility of dog genetics for understanding human disease.
Most importantly, the comparison revealed the regions of the human genome that are most highly preserved across mammals. Roughly 5 percent of the human genome has been well preserved by evolution over the past 100 million years. The researchers discovered that the most highly conserved of these sequences are not randomly distributed throughout the genome. Instead, they are crowded around just a tiny fraction (about 1 percent) of the genes that encode crucial regulatory proteins involved in development (such as transcription factors or axon guidance receptors).
"The clustering of regulatory sequences is incredibly interesting," said Kerstin Lindblad-Toh, first author of the Nature paper and co-director of the genome sequencing and analysis program at Broad. "It means that a small subset of crucial human genes is under much more elaborate control than we had ever imagined."
More than two years ago Lindblad-Toh, Lander and their colleagues embarked on a two-part project to assemble a complete map of the dog genome. First, they acquired a high-quality DNA sequence from a female boxer named Tasha, covering nearly 99 percent of the dog's genome. Using this information as a genetic "compass," they then sampled the genomes of 10 different dog breeds and other related canine species, including the gray wolf and coyote.
By comparing these dogs, they pinpointed 2.5 million individual genetic differences among breeds, called single nucleotide polymorphisms (SNPs), which serve as recognizable signposts that can be used to locate the genetic contributions to physical and behavioral traits, as well as disease.
The scientists then used the SNP map to reconstruct how intense dog breeding has shaped the genome. They discovered that selective breeding has carried large genomic regions of several million bases of DNA into breeds, creating "haplotype blocks" that are 100 times larger than those seen in the human population. "The huge genomic regions should make it much easier to find the genes responsible for differences in body size, behavior and disease," said Lander. "Such studies will need many fewer markers than for human studies. It should be like hitting the side of a barn."
Breeding programs have not only selected for desired traits, they have also had the unintended consequence of predisposing many dog breeds to genetic diseases, including heart disease, cancer, blindness, cataracts, epilepsy, hip dysplasia and deafness. With the dog genome sequence and the SNP map, scientists around the world now have the tools to identify these disease genes.
Humans suffer from many of the same illnesses as their four-legged friends and even show similar symptoms, but the genetic underpinnings have proved difficult to trace. "The genetic contributions to many common diseases appear to be easier to uncover in dogs," said Lindblad-Toh. "If so, it is a significant step forward in understanding the roots of genetic disease in both dogs and humans."
For this work, the dog-owner community is an essential collaborator. "We deeply appreciate the generous cooperation of individual dog owners and breeders, breed clubs and veterinary schools in providing blood samples for genetic analysis and disease gene mapping," said Lindblad-Toh. "Without their interest and help we could not be doing this work."
This work was funded in large part by the National Human Genome Research Institute, one of the National Institutes of Health.