NEWSFOCUS on February 20, 2010
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NEWSFOCUS on February 20, 2010 TALK ABOUT BLIND FAITH. TWENTY YEARS cause disease or genes that underlie traits Pooch politics ago, Gustavo Aguirre and his colleague Gre- such as size, coat color, or even behavior. It wasn’t always that way. In fact, it took years gory Acland were struggling to understand a And the link to humans can be direct: The top of work by a small but dedicated band of common cause of inherited blindness in 10 diseases in dogs include cancer, epilepsy, researchers for the dog’s scientific value to be dogs. They had bred affected and unaffected allergy, and heart disease—disorders that appreciated. Jasper Rine got the ball rolling individuals and traced the inheritance pat- affect many millions of people. Also, almost 20 years ago. A yeast geneticist at the www.sciencemag.org terns in the offspring, but “there was no hope because dogs live in the same environment University of California, Berkeley, he recog- of finding the gene,” recalls Aguirre, a vet- as people, they share some of the same envi- nized that dogs were bred for specific behav- erinarian at the University of Pennsylvania’s ronmental risk factors. As a result, more and iors and that those behaviors probably had a School of Veterinary Medicine in Philadel- more researchers, including a consortium very strong, and perhaps easily identifiable, phia. At the time, researchers hadn’t even genetic basis. Rine crossed Border collies assigned numbers to the canine chromo- with Newfoundlands to see if he could pin- somes, let alone begun to map the locations point the genes underlying the former’s Downloaded from of genes. Nonetheless, “I decided that in the predilection for herding and the latter’s love future, someone somewhere would come up of swimming. But he lacked a key tool: a map with [a way] to come up with the gene,” he of genetic markers—known stretches of says. So they banked blood from their dogs DNA prone to variation—that he could track and waited. from parents to offspring to determine which Their patience paid off. A decade later, were passed along with the best swimmers their freezers provided the raw material for a and which were associated with herding. The linkage map of the dog genome and, eventu- markers associated with a particular behavior ally, the discovery of the long-sought gene should lie near genes that contribute to that for progressive rod-cone degeneration. With Dogged pursuit. Elaine Ostrander helped jump- behavior. To develop such a tool, Rine con- that map as a starting point, researchers have start canine genomics. ceived the idea of a dog genome project. built a community that has proven the value For Elaine Ostrander, the timing was for- of dog genetics not just for veterinarians and about to be announced in Europe (see tuitous. She had just come to Berkeley in dog breeders but also for human geneticists. p. 1670), are turning to the dog for clues to 1990 as a postdoc to study plant genetics, and Dogs are a geneticist’s dream. Pure human genetics. “All of a sudden, people to tide her over until her new fellowship breeds, as the name implies, are often from a wide range of disciplines can see the kicked in, she took a temporary job with Rine. highly inbred for specific traits. They have value, power, and practicality of genetic Her assignment: to begin building the dog large families and well-documented studies in dogs to shed light on issues of map. She never made it to the plant lab. When genealogies, all of which greatly simplifies concern to them,” says Acland, a geneticist she left in 1993 for the Fred Hutchinson Can- the task of tracking down mutations that now at Cornell University. cer Research Center in Seattle, Washington, NAUJACK THERESA SWIFT/CORBIS; CHASE BOTTOM): TO (TOP CREDITS 1668 21 SEPTEMBER 2007 VOL 317 SCIENCE www.sciencemag.org Published by AAAS NEWSFOCUS she was a complete convert, as comfortable by Breen, Ostrander, their appetites whet- soliciting blood samples from breeders at and Francis Galibert, ted when J. Craig dog shows as she was poring over gels. Her a human geneticist Venter, then president puppy, a Border collie named Tess, became at the University of Celera Genomics in her lab’s mascot, providing Ostrander and of Rennes, France. Rockville, Maryland, her students with welcome distractions Galibert, who became turned his sequencing and, once, posing for the cover photo on convinced of the value Dog DNA deciphered. Researchers have machines on his pet Mammalian Genome. Ostrander’s home of dogs for gene sequenced this boxer’s genome. poodle, churning out a became a meeting place for colleagues inter- hunting after hearing very rough sketch of ested in promoting dog genetics. “She drove Ostrander give a talk at a Cold Spring Harbor its genome in 2001. An analysis was published this whole canine genome initiative,” says Laboratory meeting, had located markers 2 years later (Science, 26 September 2003, Matthew Breen, a cytogeneticist at North along the genome in a so-called radiation p. 1898). About the same time, the National Carolina State University’s College of Veteri- hybrid map. Ostrander and Breen added their Human Genome Research Institute (NHGRI) nary Medicine in Raleigh. markers to it to create a detailed atlas for track- at the National Institutes of Health in Bethesda, Eventually, Rine closed down his dog- ing genes. With it, researchers “could pull Maryland, began supporting the deciphering of behavior studies for lack of funding and to DNA samples from their pedigrees out of their other vertebrate genomes, and Ostrander and avoid being hassled by animal-rights freezers and begin to do genome scans,” her collaborators wasted no time writing up a activists. Ostrander persisted on the map, but Ostrander says. white paper arguing that the dog be given high progress was slow until 1996, when she, Ostrander and Aguirre had long suspected priority. She convinced the Broad Institute of Acland, and Aguirre joined forces. “We fig- that dog studies could lead to the discovery of the Massachusetts Institute of Technology and ured out we needed to check our egos at the genes important to humans. “But at the time, Harvard University in Cambridge, Massachu- door and pool our efforts,” Ostrander recalls. we were fighting the perception that dogs setts—a leader in high-throughput genome Because Aguirre and Acland had samples couldn’t tell you anything,” recalls Aguirre. sequencing and analysis—to sign on. In 2002, from a large number of dogs with known That changed in 1998, when Emmanuel the dog beat out the cat and the cow for a spot in genealogies spanning several generations, Mignot of Stanford University in Palo Alto, the sequencing pipeline. on February 20, 2010 Ostrander and colleagues were able to deter- California, and his colleagues tracked down a Ostrander put out a call to dog breeders mine the relative order of scores of markers gene that causes narcolepsy in dogs. After a for a highly inbred candidate. (The more by following which ones were inherited decade of work, they found causative muta- inbred the individual, the more similar the together in these dog families. A year after tions in the Hcrtr2 gene in narcoleptic dachs- animal’s two sets of chromosomes and the they began working together, they produced hunds, Labrador retrievers, and Doberman easier it would be to piece the genome the first map showing the positions of 150 of pinschers, a discovery that clued researchers together.) After studying hundreds of sam- these markers on the dog genome. With this in to a new molecular pathway involved in ples of dog DNA submitted by owners, tool, they quickly narrowed down the loca- sleep. With these results, “it was crystal clear Ostrander and her colleagues chose a boxer tion of the gene for progressive rod-cone that by studying dog genetics, we were going named Tasha as the first canine to have its www.sciencemag.org degeneration to a region of chromosome 9, to learn things we couldn’t learn in mice,” genome deciphered. although it would take several more years to says Ostrander. As part of that sequencing effort, get to the gene itself. That realization helped Ostrander achieve researchers at the Broad Institute compared Very quickly, that map was superseded by a her ultimate goal: a complete genome sequence Tasha’s genome with the rough draft of the much more comprehensive one, a joint effort of the dog. She and her colleagues had poodle genome and DNA sequences from nine other dog breeds and five wild canids and came up with 2.5 million single- Downloaded from nucleotide polymorphisms (SNPs): points on the genome where a change in a single nucleotide frequently occurs. The analysis, published in the 8 December 2005 issue of Nature, “is a masterpiece,” says geneticist Greg Barsh of Stanford University. Broad’s Kerstin Lindblad-Toh, who led the dog genome sequencing project, has since worked with Affymetrix in Santa Clara, Cali- fornia, to develop a SNP chip, a microarray that allows researchers to screen samples rap- idly for these variations across the genome. Dog genetics studies were primed for takeoff. These tools, says Aguirre, “put us into the 21st century.” The power of inbreeding The dog’s power in tracking genes comes largely from inbreeding. “Each [breed] is a CREDITS (TOP TO BOTTOM): GREGORY M. ACLAND; COURTESY OF NIH OF COURTESY ACLAND; M. GREGORY BOTTOM): TO (TOP CREDITS Community outreach. NHGRI’s Heidi Parker gets DNA from a dog-show competitor. mini Iceland or Finland,” explains Ostrander, www.sciencemag.org SCIENCE VOL 317 21 SEPTEMBER 2007 1669 Published by AAAS NEWSFOCUS now at NHGRI.