FEATURE ARTICLE
Genetics and the Shape of Dogs
Studying the new sequence of the canine genome shows how tiny genetic changes can create enormous variation within a single species
Elaine A. Ostrander
The Shape of Things
Our research group, along with others, has been interested for several years in identifying genes that define the differences in body size, shape and appearance between breeds. Dog breeds vary not only in overall body size, but also in leg length, head shape and many other body features, all of which are controlled at least in part at the genetic level. The amount of morphologic variation observed in the dog is reported to surpass that of all living land mammals.
The first important molecular study aimed at understanding the genetics of canine morphology was done at the University of Utah and led by Gordon Lark and Kevin Chase. The project, termed the Georgie Project in memory of a favored dog, focused on the Portuguese water dog, which is ideal for this type of study because it derives from a small number of founders, largely from two kennels, that came to the United States in the early 1950s. The breed standard permits a significant amount of variation in body size compared with other breeds. The community supporting the project is composed of highly motivated owners and breeders who have sought to improve the health of the breed through collaboration with scientists.
To date, the project has collected DNA from more than 1,000 dogs and has completed a genome-wide scan using more than 500 microsatellite markers on nearly 500 dogs. In addition to family history and medical data, more than 90 measurements have been collected for nearly 500 animals. These were derived from a set of five x-rays taken at the time of initial sample collection. Analysis of these metrics led to the development of four primary principal components (PCs), sets of correlated traits that define Portuguese water dog morphology. It is important to keep in mind that PCs are not genes but traits, and as such, they are susceptible to genetic analysis.
Analysis of the genome scan data and four PCs initially highlighted 44 putative quantitative trait loci (QTLs) on 22 chromosomes that are important for heritable skeletal phenotypes in the Portuguese water dog. QTLs derive from complicated statistical analysis and indicate locations in the genome that contribute coordinately to a particular trait. Of particular interest to us was a locus on canine chromosome 15 (CFA15) that showed a strong association with overall body size. Although this was only one of seven loci hypothesized to play a role in body size in the dog, we chose it as an initial focus because of the strength of the effect and the proximity to a compelling candidate gene.
To find the gene on CFA15, we searched for SNPs in a 15 million-base-pair region and then genotyped the resulting set of markers on all the Portuguese water dogs for which size information was available. The distribution of these markers displayed a single peak close to the insulin-like growth factor-1 gene (IGF1), which is known to influence body size in humans and mice. We investigated IGF1 in detail and showed that 96 percent of Portuguese water dog chromosomes carry one of just two patterns of alleles, which are termed haplotypes. The haplotype associated with small dogs was termed "B" and the one associated with large dogs "I." Portuguese water dogs homozygous for haplotype B—that is, dogs that have the B pattern on both chromosomes—have the smallest median skeletal size, whereas dogs homozygous for I are largest. Dogs that are heterozygous—that is, those with a different pattern on each chromosome—fall between.
To study the presumably more general role of IGF1 in size differentiation among breeds, we surveyed genetic variation associated with 122 SNPs, spanning the relevant 34 million- to 49 million-base-pair interval of chromosome 15 in 353 dogs representing 14 small breeds and 9 giant breeds. Several lines of evidence pointed to IGF1 as the gene likely to account for small body size in the dogs.
Most notably, we observed a dramatic reduction in heterozygosity in small breeds over the IGF1 gene. These results demonstrate the presence of a selective sweep in this region, showing that IGF1 has been under tight selection by breeders seeking to create ever smaller dogs. In addition, the dominance of a single unique haplotype in our panel of many unrelated small dog breeds, together with its near absence in giant breeds, suggests that the mutation is ancient and likely evolved early in the history of domestic dogs.
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