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
Dog Breeds
The domestic dog is believed to be the most recently evolved species from the family Canidae. Within the Canidae there are three distinct phylogenetic groups, or clades; the domestic dog shares a clade with the wolflike canids such as the gray wolf, coyote and jackals. Dogs are thought to have arisen perhaps as recently as 40,000 years ago, with initial domestication events occurring in eastern Asia. Most domestic breeds that we recognize today, however, likely are the product of human breeding over the last 200-300 years. Many of the most common modern breeds were developed in Europe in the 1800s. Some of the breeds represented in antiquity, including the greyhound and the pharaoh hound, are particularly interesting to study, as it is unclear whether dogs from these breeds are re-creations of ancient breeds or whether dogs alive today can truly trace their lineage to founders from thousands of years ago.
The American Kennel Club (AKC) currently recognizes about 155 breeds of dog, but new breeds are created and given breed-recognition status frequently. What defines a dog breed? Although a dog's parentage can be recognized by its physical attributes—coat color, body shape and size, leg length and head shape, among others—the concept of a breed has been formally defined by both dog fanciers and geneticists.
Dog regulatory bodies such as the AKC define an individual's breed by its parentage. For a dog to become a registered member of a breed (say, a golden retriever), both of its parents must have been registered members of the same breed, and their parents in turn must be registered golden retrievers. As a result, dog breeds in the United States today are generally closed breeding populations with little opportunity for introduction of new alleles (variations in the genome). At a genomic level, purebred dogs are usually characterized by reduced levels of genetic heterogeneity compared to mixed-breed dogs. Breeds that derive from small numbers of founders, have experienced population bottlenecks or have experienced popular-sire effects—that is, the effect on the breed of a dog who does well in shows producing a disproportionate number of litters—display further reductions in genetic heterogeneity.
Recently, my laboratory group and others have begun to use genetic tools such as markers to define the concept of a dog breed. A genetic marker is a position in the genome where there is variability in the sequence that is inherited in a Mendelian fashion (that is, following the rules of classical genetics). Two common kinds of markers are microsatellite markers, where the variation comes from the number of times a repeat element is reiterated at a given position on a chromosome, and single-nucleotide polymorphisms (SNPs, pronounced "snips"), in which the DNA sequence varies when a single nucleotide (denoted A, C, T or G) in a sequence differs between the paired chromosomes of an individual.
These alterations are proving invaluable for understanding the role of genetic modifications both within and between breeds. Because the alleles of markers are inherited from parent to child in a Mendelian fashion, they can be used to track the inheritance of adjacent pieces of DNA through the multiple generations in a family. There are thousands of microsatellite markers and millions of SNPs distributed randomly throughout the canine genome.
In order to determine the degree to which dogs could be assigned correctly to their breed group, my lab utilized data from 96 microsatellite markers spanning all the dog's 38 autosomes in a set of 414 dogs representing 85 breeds. We found, first, that nearly all individual dogs were assigned correctly into their breed group when we used a set of statistical tools called clustering algorithms, which look for similarities in the frequency and distribution of alleles between individuals. The exceptions largely included six sets of closely related breed pairs (for example whippet-greyhound and mastiff-bullmastiff) that could only be assigned to their respective breeds when considered in isolation from other breeds.
We also showed that the genetic variation between dog breeds is much greater than the variation within breeds. Between-breed variation is estimated at 27.5 percent. By comparison, genetic variation between human populations is only 5.4 percent. Thus the concept of a dog breed is very real and can be defined not only by the dog's appearance but genetically as well.
A second part of the study used an assignment test to determine whether we could correctly identify each dog's breed by its genetic profile alone. In a blinded study, where the computer program did not know what data set came from which breed, 99 percent of dogs were correctly assigned to their breed based on their DNA profile alone.
To determine the ancestral relationship between breeds, Heidi Parker from my lab used data from the same set of dogs and sought to determine, ideally, which dog breeds were most closely related to one another. To do this we utilized a computer program called structure, which was developed by Jonathan Pritchard at the University of Chicago and his colleagues. The program identifies genetically distinct subpopulations within a group based on patterns of allele frequencies, presumably from a shared ancestral pool.
The structure analysis initially ordered the 85 breeds into four clusters, generating a new canine classification system. Cluster 1 comprised dogs of Asian and African origin—thought to be older lineages—as well as gray wolves. Cluster 2 included largely mastiff-type dogs with big, boxy heads and large, sturdy bodies. The third and fourth clusters split a group of herding dogs and sight hounds away from the general population of modern hunting dogs, the latter of which includes terriers, hounds and gun dogs. As more dog breeds have been added to the study, additional groupings have emerged.
These data are extremely useful for disease-gene mapping studies. In some cases, dogs from breeds that are members of the same cluster can be analyzed simultaneously to increase the statistical power of the study. This will not only aid in the identification of genomic regions in which the disease gene lies, but will also assist in "fine mapping" studies which aim to reduce the region of DNA linkage to a manageable size of about 1 million bases. Once a region is well defined, we can begin to select candidate genes for mutation testing.