Dog genome researchers track paw prints of selective breeding

With more than 400 distinct breeds, dogs come in a wide range of shapes, sizes, fur-styles, and temperaments. The curly-haired toy poodle, small enough to sit in a teacup, barely looks or acts like the smooth-coated Great Dane tall enough to peer like a periscope out of a car's sunroof. Not so apparent are breed differences in how the dogs' bodies function and their susceptibility to various diseases.

Although domestication of dogs began over 14,000 years ago, according to Dr. Joshua Akey, University of Washington (UW) assistant professor of genome sciences, the spectacular diversity among breeds is thought to have originated during the past few centuries through intense artificial selection of and strict breeding for desired characteristics. Akey is the lead author of the effort to map canine genome regions that show signs of recent selection and that contain genes that are prime candidates for further investigation. Those genes are being examined for their possible roles in the most conspicuous variations among dog breeds: size, coat color and texture, behavior, physiology, and skeleton structure.

The researchers performed the largest genome-wide scan to date for targets of selection in purebred dogs. The genomes came from 275 unrelated dogs representing 10 breeds that were very unlike each other. The breeds were: Beagle, Border Collie, Brittany, Dachshund, German Shepherd, Greyhound, Jack Russell Terrier, Labrador Retriever, Shar-Pei, and Standard Poodle.

The study was conducted, the researchers said, because the canine genome, the product of centuries of strong selection, contains many important lessons about the genetic architecture of physical and behavioral variations and the mechanisms of rapid, short-term evolution. The findings, the researchers said, "provide a detailed glimpse into the genetic legacy of centuries of breeding practices."

Their results were published Jan. 11 in the Proceedings of the National Academy of Science, in the article "Tracking footprints of artificial selection in the dog genome."

The researchers catalogued more than 21,000 tiny variations in the genome. In investigating the relationships among the 10 breeds, they found that, genetically, the German Shepherd, Shar-Pei, Beagle, and Greyhound were especially distinct.

Their list of most differentiated regions of the dog genome included five genes already linked to hallmark traits of certain breeds: one for small size, one for short limbs like those in Dachshunds and other stubby-legged dogs, and three for coats.

In calculating the overlap of the signatures marking selection in the genome, the researchers found that approximately 66 percent occurred in only one or two breeds. They noted it was likely that these genome regions contain genes that confer qualities that distinguish a breed, such as skin wrinkling in the Shar-Pei. In contrast, signatures of selection found in five or more breeds tended to sort the dogs into classes, and include, for example, a gene that governs the miniature size of breeds in the toy group.

A gene associated with dwarfism in mice, the study reports, appears to mediate variations in dog breed size and weight. Small-size breeds, like Dachshund, Beagle, Jack Russell Terrier, and Brittany have enormous differentiation in this gene, compared to larger-size breeds. Another region of peak differentiation in the dog genome, in an area thought to regulate muscle cell formation in embryos, seems to separate the German Shepherd, Jack Russell Terrier, Border Collie and Greyhound from the Dachshund, Beagle, Brittany, and Shar-Pei.

The 155 regions of the genome that appear to have been influenced by selective breeding contain 1,630 known or predicted protein-coding genes. The researchers tried to obtain a broad overview of the molecular functions of these genes. The were surprised to discover that genes involved in immunity and defense were overrepresented in the 155 regions, a phenomenon also discovered in genome analysis of selection in natural populations. Natural and artificial selection were not expected to act on similar classes of genes, the researchers noted, but immune-related genes may be frequent targets of selection because of their critical role in defending against ever-changing infections.

The researchers honed in on a particular genome region in the Shar-Pei. Many of these dogs have excessive wrinkles, but some are smooth. The degree of skin folding correlates with levels of certain molecules whose production may be governed by a gene in this region. Rare mutations in this same gene also cause severe skin wrinkling in people. Tiny genetic variations in this gene seemed linked to whether a Shar-Pei would be smooth or wrinkled, and a rare genetic mutation was found in the Shar-Pei but not in other dogs.

The researchers explained, that, despite the many insights emerging from their data, there were several limitations to their study and in interpreting the findings. They pointed out that a pattern of variation that is unusual to the dog genome at large doesn't prove that specific genome region is under selection.

A major impetus behind studying dog genomics, the researchers pointed out, is its potential to advance knowledge about the genetic basis of human form variations and of differences in disease susceptibility among people. In many cases, the researchers said, it may be easier to locate the genetic targets of selection in dogs, and then map these to related regions in the human genome. Scientists are intrigued by the possibility that recent selection may have affected genome regions common to both human and dog lineages.

"This research has shown that artificial selection in dogs has acted on many of the same genes as natural selection in humans, and that many of these genes are regulators of gene activity," said Dr. Irene Eckstrand, who oversees evolution grants at the National Institute of General Medical Sciences at the National Institutes of Health. "The statistical and computational approaches used in this study will be of great value in deciphering the organization of human genetic variation, and in identifying the genetic basis of human characteristics."

The researchers also said that a better understanding of artificial selection in dogs may reveal the molecular mechanisms of rapid, short-term evolution. Future work, they hope, may uncover the gene activities responsible for shaping the incredible diversity among the world's dogs.

In addition to Akey, the researchers on the study were Alison L. Ruhe, Aaron Wong, and Mark W. Neff of the Center for Veterinary Genetics at the University of California, Davis; and Dayna T. Akey, Caitlin F. Connelly, Jennifer Madeoy, and Thomas J. Nicholas, all of the UW Department of Genome Sciences. Neff is also affiliated with the Center for Canine Health and Performance, Translational Genomics Institute, Phoenix, and the Van Andel Research Institute in Grand Rapids, Mich.

The project was funded by a grant from the National Institutes of Health and a Sloan Fellowship in Computational Biology.