REVIEWS Leader of the pack: gene mapping in dogs and other model organisms Elinor K. Karlsson*‡ and Kerstin Lindblad-Toh*§ Abstract | The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. We share many diseases with our canine companions, including cancer, diabetes and epilepsy, making the dog an ideal model organism for comparative disease genetics. Using newly developed resources, whole-genome association in dog breeds is proving to be exceptionally powerful. Here, we review the different trait-mapping strategies, some key biological findings emerging from recent studies and the implications for human health. We also discuss the development of similar resources for other vertebrate organisms. Population bottleneck Understanding the genetic basis of human disease is one old, and thus have long linkage disequilibrium (LD) and A marked reduction in of the greatest challenges of biomedical research1. Using long haplotype blocks, making them particularly amenable population size followed by the an appropriate model organism avoids many difficulties to genome-wide association (GWA) mapping with fewer survival and expansion of a inherent to human-based studies. Since the beginning markers and fewer individuals compared with humans. small random sample of the original population. of the twentieth century, the foremost model for genetic However, the domestic dog population is ancient, dating studies in mammals has been the mouse, which boasts back approximately 15,000 years, and thus has short LD Linkage disequilibrium an impressive array of experimental resources2–5. As a and short haplotype blocks. Examining an associated (LD). Non-random association model for complex human disease, however, the mouse locus in several breeds carrying the same mutation can of alleles at two or more loci. has significant limitations. Many diseases that occur identify a small region that is comparable in size to those Haplotype block spontaneously in humans must be induced in laboratory found in human studies. A haplotype is the combination mice. Whereas complex human disease is polygenic, the Geneticists have long recognized the exceptional of alleles observed for one or genetic manipulations in mice test the effect of a single characteristics of the domesticated dog and by the more consecutive markers on a major gene. Conditional and partial knockouts provide 1990s had begun mapping traits. Originally, large mul- chromosome. A haplotype block is the region of a some flexibility, but studying the interaction between tigenerational canine pedigrees were used to focus on chromosome that contains no multiple genes remains difficult. The mouse is ideal for highly penetrant Mendelian phenotypes. Using simple recombination. studying a putative mutation, once it has been found, but sequence length polymorphism linkage mapping12, canine it is less useful for finding those mutations to start with. geneticists found loci for progressive retinal atrophy13,14, When considering other model organisms, the copper toxicosis15,16, renal cancer17,18 and narcolepsy19,20. domestic dog immediately springs to mind as an ideal Traits with complex inheritance, however, remained out *Broad Institute of Harvard model for mapping human complex diseases, as it has of reach. and Massachusetts Institute both a similar spectrum of diseases and an advantageous When developing an experimental organism, it is of Technology, 7 Cambridge 6 (BOX 1) Center, Cambridge, population structure . The modern dog is the important to carefully design strategies and tools on 7 Massachusetts 02142, USA. most physically diverse domesticated species , encom- the basis of the traits of interest in the model in ques- ‡FAS Center for Systems passing over 400 breeds8. Each of these breeds is defined tion, as well as its population history and genome Biology, Harvard University, by specific behavioural and physical characteristics structure. Thus, the Dog Genome Sequencing Project, 7 Divinity Avenue, Cambridge, (REF. 21) Massachusetts 02138, USA. that have been driven to exceptionally high frequency completed in 2005 , focused not just on sequenc- 9 §Department of Medical by population bottlenecks and strong artificial selection . ing the genome but also on generating the resources Biochemistry and This process had unintended consequences on the health needed for association mapping, which include an Microbiology, Uppsala of pure-bred dogs, with high rates of specific diseases in understanding of canine haplotype structure and a University, BOX 597, 751 24 certain breeds reflecting enrichment of risk alleles owing dense SNP map. Currently, the tools for high-throughput Uppsala, Sweden. Correspondence to K.L.-T. to random fixation during bottlenecks, hitch-hiking SNP genotyping of the dog have been developed and e-mail: [email protected] of mutations near desirable traits and pleiotropic effects of several genes have already been mapped, including doi:10.1038/nrg2382 selected variants10,11. Most breeds are less than 200 years microphthalmia-associated transcription factor (MITF) NATURE REVIEWS | GENETICS VOLUME 9 | SEPTEMBER 2008 | 713 REVIEWS 25–28 Genome-wide association for white coat colour and a duplicated cluster of fibro- hairlessness, barking and haemophilia . Following (GWA). An approach that tests blast growth factor (FGF) genes underlying a defect in advances in genetics, canine geneticists incorporated the whole genome for a spinal development22,23. cytogenetic and chromosomal techniques into this statistical association between Given that humans and dogs share many diseases, search for the cause of dog phenotypes. In 1989, DNA a marker and a trait in unrelated cases and controls. finding the causative loci in dogs can identify genes and sequencing identified the first genetic variant for an pathways relevant to the disease in humans, potentially inherited canine disorder — a point mutation underly- Simple sequence length offering novel treatment targets. In addition, dissecting ing haemophilia B24,29. In 1997, linkage mapping using polymorphism the network of interacting loci that cause diseases with microsatellite markers identified a marker for a canine Short tandem repeats of DNA complex, polygenic inheritance in dogs, and defining disease, copper toxicosis, in Bedlington terriers15. By that vary in length. their severity, will give insight into the considerably the end of that year, the first genetic linkage map of the Linkage mapping more complex web underlying human diseases. dog genome, containing 150 microsatellite markers, A mapping method which uses In this article, we review the steps necessary to take was complete30. The identification of a gene for canine pedigrees to find broad full advantage of the domestic dog for both quantitative narcolepsy in 1999 intensified interest in the dog as a genomic regions (10–20 20 centimorgans) that adhere to and medical trait mapping, and the implications of the model for human disease . The following years saw sev- an inheritance model proposed results for human biology and health. We also discuss eral larger-scale projects reach completion, following in for the trait of interest. the process of generating the appropriate genetic and the footsteps of the Human Genome Project in resource genomic tools for the dog and how this translates to building31–34. Finally, with the Dog Genome Sequencing other vertebrate organisms with different biology and Project (described in detail below), scientists were in a population history. position to carefully consider what state-of-the-art tools should be developed to map traits in the dog. Developing the tools for trait mapping Today, a robust set of canine genetics resources exist Dog breeds have fascinated geneticists since at least that facilitate the search for genetic variants underly- the beginning of the 1900s, when the first inherited ing diseases and other phenotypes at all stages. These disorders in dogs were described24. Between 1910 and include: defining phenotypes and selecting sample sets; 1950, the Journal of Heredity alone published numerous identifying trait loci through linkage, association or articles on dogs, covering topics as diverse as coat colour, selection mapping; identifying gene function and genomic variants; and testing likely variants for function. Box 1 | The dog as a model for human disease A genome sequence and SNP map. When the canine The similarities between canine and human diseases are striking and have been genetics community and the Broad Institute of Harvard thoroughly reviewed70. Here we summarize a few key features in which dogs excel, and Massachusetts Institute of Technology proposed including similarity in disease manifestation, genome content, genetic sequencing the dog genome, they considered carefully predisposition, treatment and clinical trials. how to best complement existing resources and make In dogs, just as in humans, diseases occur spontaneously over the course of their full use of the dog and its advantageous population lives and include many common human diseases, such as cancers, diabetes, heart history (FIG. 1). Thus, the Dog Genome Sequencing disease, eye diseases, epilepsy, deafness and even psychiatric diseases such as Project21 included meticulously designed experiments obsessive compulsive disorder71–75. Clinical manifestations in dogs and humans are that explored the haplotype structure of the dog genome often similar. For example, the progression of osteosarcoma is nearly identical