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 , , NAUJACK THERESA SWIFT/CORBIS; CHASE BOTTOM): TO (TOP CREDITS

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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, 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,

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now at NHGRI. Many breeds stem from a few five genetically defined groups, with some individuals whose progeny were interbred, not subdivisions within each group. because of geographic isolation but to select As these researchers will report, they have for specific features and behaviors. As a used these relationships to track down a gene result, members of a given breed have causing collie eye anomaly, which is the extremely long stretches of identical DNA in canine equivalent of a human birth defect in common—millions of bases long compared which part of the eye does not form properly. to the typical tens of thousands of bases in In 2003, they had narrowed the gene’s loca- humans. In humans, “there’s a lot of back- tion down to a 1.7-million-base stretch of dog ground cackling, but when you look at the dog chromosome 37. Then they went further: “By Born to point. Even as puppies, German genome, the message is loud and clear, with- shorthaired pointers live up to their names. comparing different herding breeds with the out a lot of background noise,” Breen same disease, we whittled down [the possibil- explains. That means researchers can track ities] to four genes,” Ostrander explains. down recessive genes involved in disease Mark Neff of the University of California, A close look revealed the likely culprit: a using many fewer animals. They also need an Davis, explains. Breeds derived from a com- gene called NHEJ1 missing 7800 bases. They order of magnitude fewer SNPs than are mon ancestral breed might share a mutation, found the same mutation in two more dis- needed for human studies. but distantly related breeds will not, offering tantly related breeds, Nova Scotia duck The inbreeding in dogs is especially valu- the potential of revealing other genes, perhaps tolling retrievers and longhaired whippets, able in studies of genetic risks in complex dis- in the same pathway involved in a disease. which likely had farm collies in their family eases. In people, different mutations, even dif- To help sort out how different breeds are trees. But unrelated soft-coated wheaten ter- ferent genes, may be at fault in the same dis- related to each other, Ostrander, Heidi Parker riers, which also get this disease, don’t have ease. Dozens of genes contribute to the risk of in her lab, and their colleagues have looked the mutation. “We think we will be able to common cancers, for example, with no single for genetic variants that are shared across play that trick [of looking for mutations in one jumping out as key. But because each dog breeds: The more shared variants, the more closely related breeds] again and again,” says

breed is an isolated, inbred population that closely the breeds are related. They initially Nathan Sutter, who recently left Ostrander’s on February 20, 2010 typically dates back just a few hundred years, studied 85 breeds, and the results helped them lab for Cornell University. not a lot of time has passed for the dogs in any home in on a gene for short stature (Science, PhyDo is also helping Ostrander’s group one breed to develop multiple mutations for 6 April, p. 112). They have now expanded the make sense of bladder cancers. Five breeds the same disorder, or for several mutations to work—called the PhyDo Project—to 130 of tend to develop this cancer. The most suscep- have been introduced from outbreeding. “In the 155 breeds recognized by the American tible, with a 30-fold increase in risk, is the dogs of one breed, you will have exactly the Kennel Club. In work in press at Genome Scottish terrier. Three other at-risk breeds same mutation in the same gene,” geneticist Research, they report that breeds cluster into are terriers, which likely share the same

Europe Going to the Dogs www.sciencemag.org While U.S. researchers were beginning to piece together the first genetic maps for dogs in the 1990s, University of Copenhagen pig researcher Merete Fredholm was wringing her hands in frustration at the lack of funds to support a European consortium with the same goal. But now, she and collaborators from more than 20 institutions are poised to make a champion showing in this field, thanks to a pending European Union award for about $16 million. Downloaded from Named after the legendary wolf who nourished the founders of Rome, the LUPA consortium plans to get DNA samples and health histories from 8000 dogs and hunt down genes for 18 diseases, including four cancers, four inflammatory disorders, and three heart diseases. “We have decided to focus on certain areas and to standardize the clinical characterization of these diseases,” explains Leif Andersson, a geneticist at Uppsala University in Sweden. In this way, they use the DNA from animals across different coun- Best of Show. Olle Kämpe, Göran Andersson, Kerstin Lindblad-Toh, Åke tries, as well as across different breeds, to find genes. Once they have found Hedhammar, and Leif Andersson (left to right) have teamed up to tackle the gene, they plan to see what role it plays in humans, says LUPA coordina- human diseases through dog studies. tor Michel Georges of the University of Liege in Belgium. Georges is a recent convert, having never studied dogs before. But join- ance for pets to sort out which individual dogs and breeds are best suited for ing him are key players in canine genomics. Kerstin Lindblad-Toh, who particular gene searches. headed the dog sequencing project at the Broad Institute of Massachusetts The European effort promises to push the field to warp speed. “We’re Institute of Technology and Harvard University in Cambridge, Massachu- going to learn a lot more about a lot of diseases,” says Elaine Ostrander, setts, is now spending three-quarters of her time at Uppsala University. “Her a geneticist at the National Human Genome Research Institute in recognition, competence, and working capacity will change [European dog Bethesda, Maryland. Until recently, much of the high-profile work on dog genomics],” says collaborator Åke Hedhammar, a long-term dog researcher genetics came from Ostrander and her collaborators, but already Europe at the Swedish University of Agricultural Sciences in Uppsala, who has used is churning out a slew of key papers. With LUPA, “there will be a lot of kennel club records and records from companies that provide health insur- competition,” says Fredholm. –E.P. CREDITS (TOP TO BOTTOM): DALE C. SPARTAS/CORBIS; ERIK BONGCAM ERIK SPARTAS/CORBIS; C. DALE BOTTOM): TO (TOP CREDITS

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mutation. But PhyDo data verify that the fifth that is mutated in humans with Waardenburg lem is identifying the phenotype and separat- susceptible breed, the beagle, is not at all syndrome, an inherited disease characterized ing what is learned versus what they are born related, so its bladder tumor risk probably by hearing loss and skin and pigmentation with,” says Parker. Adds Barsh: “We know stems from a different genetic abnormality. abnormalities, and in several mouse pigmen- whether [a dog] is yellow or black, but some- tation disorders. A second study on Rhode- times it’s not so easy to tell how good a dog is Dog fanciers sian ridgebacks has led the group to a muta- at herding versus retrieving.” In Ostrander’s Ostrander’s group is working with Carlos tion possibly involved in neural tube defects; lab, Tyrone Spady—who used to study visual Bustamante of Cornell University to make that study required fewer than two dozen ani- behavior in fish—depends on DNA from dogs SNP profiles of individual breeds available in mals as well. “It shows how little material you that live in different places, with different a public database called “CANMAP.” It need,” says Åke Hedhammar, a geneticist at upbringings and lifestyles. So Spady asks should provide researchers and breeders with the Swedish University of Agricultural Sci- owners to fill out questionnaires: how fre- powerful tools to track down the traits in ences in Uppsala. quently does the dog chase other animals, what which they are most interested. Already, He and Lindblad-Toh expect to make quarry gets it running, and so on. By pooling researchers are intrigued by the possibilities. progress understanding more complex dis- surveys from many people, he corrects for bias The data set includes wolves, the common eases as well. For example, boxers, bull terri- in the owners’ responses and uses the data in ancestor of all dogs, which should give evolu- ers, and West Highland white terriers are genomewide association studies. tionary biologists a “wonderful perspective At the Norwegian School of Veterinary Sci- on the evolution of the dog,” says collaborator ence in Oslo, Frode Lingaas is taking a similar Robert Wayne, an evolutionary biologist at tack in looking into “cocker rage.” In this syn- the University of California, Los Angeles. drome, generally amiable pets turn on their Since the 1980s, he’s wanted to find the genes owners, exhibiting frighteningly aggressive underlying the evolution of dogs and dog behavior. He and his European colleagues breeds. Back then, “it was clear we didn’t assess the dogs’ personalities through inter- have the technology to address the basic ques- views with the owners and questionnaires.

tions,” he recalls. Now, says Sutter, by com- Several hundred samples will come from Eng- on February 20, 2010 paring SNP profiles of dogs and wolves, “we lish cocker spaniels, but a few will come from will know what changes occurred in the dog English springer spaniels, which are also prone during domestication.” to this mental disorder. These dogs should get Stanford’s Barsh has a different quarry the researchers close to the gene, and a com- in his sights. Over the past 15 years, parison with golden retrievers, which can also he has worked on the genetics be four-legged Jeckylls and Hydes, should get of coat color in mice, but them within striking distance. Because rage is recently he’s focused on dogs often a symptom in schizophrenia, bipolar dis-

and is well on his way to under- ease, obsessive-compulsive disorder, and other www.sciencemag.org standing the genetic basis of the mental problems, finding this gene could help stripes in the brindle coat of Great Common ills. Dogs and researchers understand why it develops in Danes. Like Barsh, Danielle humans suffer from many of patients with mental illness. Karyadi in Ostrander’s lab is also a the same diseases, such as Swedish researchers have a leg up on recent convert to dog genetics. She atopic dermatitis (left). Spady and Lingaas. In Sweden, breeders has spent much of her career chasing often evaluate their young dogs using a stan- down genes that make people more prone to atopic dermatitis, a skin disease dardized personality test. By looking at Downloaded from susceptible to prostate cancer. Now, that in both dogs and humans has environ- aggression, boldness, shyness, and sociabil- she has turned her attention to squamous mental and genetic components. Genetic ity, they are able to better assess which ones cell carcinoma, a cancer found only in solid studies are under way in these breeds to find should be trained as working dogs and for black dogs, such as poodles. “It will be the genes that influence this risk. what jobs. So they have a large data set to really exciting when we can identify genes work with and are moving forward with those in dog cancers” and use them to understand A window on behavior studies, says Hedhammar. And in Russia, a human cancers, says Karyadi. The rapid progress in dog genetics is prompt- long-term breeding program in foxes has Lindblad-Toh has also been won over to ing some researchers to get back to studies yielded docile, doglike animals whose genes the hounds. She specialized in human genet- that motivated a canine genome project in the might yield insights into what makes dogs so ics when she came to Cambridge but by first place: tracking down genes associated affectionate and loyal. chance got roped into running the mouse with behavioral traits. Neff has teamed up Although Ostrander is curious about the genome sequencing project and eventually with Illumina Inc. in San Diego, California, to genetic basis of why dogs get sick, grow tall, all mammalian sequencing projects at the use a microarray to look for SNPs associated or excel at hunting, the intimacy she and oth- Broad Institute. Working with European col- with “pointing.” About 40 breeds point— ers share with their canine pets is not some- laborators, Lindblad-Toh’s group has two freezing and lifting a paw in the direction of a thing she cares to be intellectual about. Just papers in press demonstrating the power of rabbit or other quarry. “I finally feel we have a the thought of the death of her lab’s mascot a genomewide association studies in dogs to chance to understand the behavior,” says Neff, year ago still brings tears to her eyes. “There’s pin down genes. In one, they used fewer than who worked with Rine in the 1990s. some genetics buried in that,” she says, “but I two dozen boxers to track down the gene for Even with the best genetic resources, how- am going to leave that to someone else.”

CREDITS (TOP TO BOTTOM): KERSTIN BERGVALL; LESTER V. BERGMAN/CORBIS V. LESTER BERGVALL; KERSTIN BOTTOM): TO (TOP CREDITS white coat color. The gene is the same one ever, the work is still challenging. “The prob- –ELIZABETH PENNISI

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