Man's best friend becomes biology's best in show: genome analyses in the domestic dog

Abstract

In the last five years, canine genetics has gone from map construction to complex disease deconstruction. The availability of a draft canine genome sequence, dense marker chips, and an understanding of the genome architecture has changed the types of studies canine geneticists can undertake. There is now a clear recognition that the dog system offers the opportunity to understand the genetics of both simple and complex traits, including those associated with morphology, disease susceptibility, and behavior. In this review, we summarize recent findings regarding canine domestication and review new information on the organization of the canine genome. We discuss studies aimed at finding genes controlling morphological phenotypes and provide examples of the way such paradigms may be applied to studies of behavior. We also discuss the many ways in which the dog has illuminated our understanding of human disease and conclude with a discussion on where the field is likely headed in the next five years.

Figure 1

An unsupervised cluster analysis of dogs and wolves. Using clustering algorithms with more than 43,000 single-nucleotide polymorphisms (SNPs), 85 dogs, representing 85 different breeds, along with 43 wolves from Europe and Asia, were assigned to 2–5 populations (inner circle to outer circle, respectively) based solely on genomic content. Each column represents a single individual divided into colors representing genomic populations. Blue indicates a wolf-specific signature, and red indicates a dog-specific signature. Note that the majority of crossover lies between ancient dog breeds and Chinese or Middle Eastern wolves. Figure originally published in Nature (158).

Figure 2

Variation in dog breeds encompasses a large range of sizes, shapes, colors, and behaviors. Breeds (and behaviors) are listed from the upper left, clockwise: Border collie (herding: controlling the movement of livestock is one of the oldest described behaviors in dogs), Pug dog (companionship: one of the most prized traits a dog provides), Whippet (coursing: chasing small or large game, a natural forerunner to racing), Alaskan sled dogs (mushing: pulling a sled with driver as a member of a team for either sport or transportation), German shorthaired pointer (pointing: identifying the location of game), Foxhounds (tracking: working as a pack to follow scent of moving game and signal the hunter), Portuguese water dog (water retrieval: used on fishing boats to bring in nets and line, round up fish, and deliver messages between boats), Bernese mountain dog (drafting: pulling heavy loads individually or in pairs, usually to transport goods). Herding picture provided courtesy of paurian@flickr.

Figure 3

Average linkage disequilibrium (LD) in 20 dog breeds sorted by breed population size. The breeds are listed at the left of the graph, followed by the number of dogs registered in the breed in 2009. LD was calculated at five unlinked loci by Sutter et al. and Gray et al. (50, 144). Linear trend line indicates overall tendency for LD to increase with a decrease in population size. Breeds that display considerable deviations from the trend likely have complex population histories involving multiple changes in population size, admixture, and/or changing selective pressures.

Figure 4

Regions of homozygosity and heterozygosity as found through direct sequencing of the boxer genome. All 38 autosomes and the X chromosome were sequenced from a female boxer to produce a 7.8x draft sequence. Heterozygous or homozygous state of each contig in the genome build was assessed though examination of approximately 770,000 single-nucleotide polymorphisms (SNPs) with heterozygous = 1 SNP in 1000 bps versus homozygous = 1 SNP in 20,000 bps. Contigs with the same state were merged to form blocks. Average size of the light-blue homozygous blocks is 6.9 Mb. Average size of the dark-blue heterozygous blocks is 1.1 Mb. White blocks indicate the centromeres. All canine chromosomes except the X are telocentric. Figure originally published in Nature (88).

Figure 5

Haplotype shared among ten breeds of dog reduced the progressive rod-cone degeneration (prcd) locus from 1.5 Mb to 106 Kb. An identical haplotype spanning 106 Kb was found in miniature and toy poodles, English cocker spaniels, American cocker spaniels, Labrador retrievers, Portuguese water dogs, Chesapeake Bay retrievers, Nova Scotia duck tolling retrievers, Australian cattle dogs, and American Eskimo dogs with allelic forms of prcd. The causative mutation was identified in a novel gene, now called PRCD, located between CYGB and ST6GALNAC2 (165). The top row shows a schematic of the chromosome region with genes named above. Below the chromosome are the bacterial artificial chromosomes (BACs) used to tile sequence across the interval. The haplotypes are shown with common alleles colored yellow, and a change in color indicates a recombination event or change in haplotype. Solid dots indicate deleted nucleotides. Names of tagging markers used for genotyping are given at the bottom of the haplotype chart. Figure originally published in Genomics (49) and reprinted with permission from Elsevier.

Figure 6

Seven different coat phenotypes are created through the allelic variation at three genes. Protein altering mutations in FGF5 and KRT71 along with changes in expression levels of RSPO2 combine to create the seven coat types displayed. The combinations of alleles are displayed to the right of the coat type. The coat types represented by each breed are as follows; (a) short, (b) wire, (c) curly-wire, (d) long, (e) long with furnishings, (f) long and curly, (g) long and curly with furnishings. Figure originally published in Science (20).