The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs. We identified 155 genomic regions that possess strong signatures of recent selection and contain candidate genes for phenotypes that vary most conspicuously among breeds, including size, coat color and texture, behavior, skeletal morphology, and physiology. In addition, we demonstrate a significant association between HAS2 and skin wrinkling in the Shar-Pei, and provide evidence that regulatory evolution has played a prominent role in the phenotypic diversification of modern dog breeds. Our results provide a first-generation map of selection in the dog, illustrate how such maps can rapidly inform the genetic basis of canine phenotypic variation, and provide a framework for delineating the mechanistic basis of how artificial selection promotes rapid and pronounced phenotypic evolution.

Coat color and type are essential characteristics of domestic dog breeds. Although the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability, we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin–2, fibroblast growth factor–5, and keratin-71, respectively), that together account for most coat phenotypes in purebred dogs in the United States. Thus, an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes.

A mutation in the canine multidrug resistance gene, MDR1, has previously been associated with drug sensitivities in two breeds from the collie lineage. We exploited breed phylogeny and reports of drug sensitivity to survey other purebred populations that might be genetically at risk. We found that the same allele, mdr1-1⌬, segregated in seven additional breeds, including two sighthounds that were not expected to share collie ancestry. A mutant haplotype that was conserved among affected breeds indicated that the allele was identical by descent. Based on breed histories and the extent of linkage disequilibrium, we conclude that all dogs carrying mdr1-1⌬ are descendants of a dog that lived in Great Britain before the genetic isolation of breeds by registry (ca. 1873). The breed distribution and frequency of mdr1-1⌬ have applications in veterinary medicine and selective breeding, whereas the allele's history recounts the emergence of formally recognized breeds from an admixed population of working sheepdogs.allele age ͉ Canis familiaris ͉ drug sensitivity ͉ identity by descent ͉ P-glycoprotein T he introduction of a new parasiticide in the 1980s (1) uncovered a preexisting mutation in dogs that predisposes animals to a potentially fatal neurotoxicosis (2, 3). The drug, ivermectin, exerts antiparasitic action by potentiating ligandgated chloride ion channels in the peripheral nervous system of several invertebrate phyla (4-7). The resulting influx of chloride ions silences synaptic transmissions, thereby causing lethal paralysis in nematode and arthropod parasites. Ivermectin is generally safe for use in domestic animals because the homologous mammalian targets are restricted to the CNS (8, 9) where they are shielded by the blood-brain barrier (reviewed in ref. 10). A principal component of this protective barrier is Pglycoprotein, an ATP-dependent drug transporter that moves a broad spectrum of substrates across several important tissue borders (11). P-glycoprotein is encoded by the multiple drug resistance gene, MDR1.The earliest indication that ivermectin neurotoxicity was caused by a defect in the blood-brain barrier came from an observation that affected dogs had elevated concentrations of ivermectin in the CNS (12). Almost a decade later, a similar phenotype was observed in knockout mice lacking Abcb1a, the murine ortholog of MDR1 (13). Mealey et al. (14) investigated canine MDR1 as a candidate gene for ivermectin sensitivity and discovered that affected Collies were homozygous for a 4-bp deletion in the fourth exon. The mutation, mdr1-1⌬, causes a frameshift accompanied by multiple premature stop codons, presumably resulting in a severely truncated P-glycoprotein composed of Ͻ10% of the wild-type amino acid sequence. This allele probably results in a complete loss of Pglycoprotein function, although this fact has not yet been formally established (15). More than 20 therapeutic drugs are known substrates of P-glycoprotein. Recently, three of these drugs were found to interact with mdr1-1⌬ and cause toxic reac...