Population Structure of 85 Dog Breeds

Fig. 2 Population structure of the domestic dog. Figure is derived from the work of Parker et al. (2004). Five dogs from each of 85 breeds were genotyped using 85 (CA)n repeat-based microsatellites. Markers spanned all autosomes at 30 Mb density. Analysis was performed using the computer program structure. Analysis at K = 2, 3, and 4 divided the population of 85 breeds into the most likely groups based on allele sharing. Group 1 is comprised largely of Asian breeds such as the Lhasa Apso, Shar Pei, and Akita. Group 2 is the mastiff group and includes, for example, the Boxer, Bull Dog, and Presa Canario. Group 4 includes a mixture of dogs including working breeds. Group 4 is enriched for sight and scent hounds and includes breeds such as the spaniels and retrievers

Fig. 2 Population structure of the domestic dog. Figure is derived from the work of Parker et al. (2004). Five dogs from each of 85 breeds were genotyped using 85 (CA)n repeat-based microsatellites. Markers spanned all autosomes at 30 Mb density. Analysis was performed using the computer program structure. Analysis at K = 2, 3, and 4 divided the population of 85 breeds into the most likely groups based on allele sharing. Group 1 is comprised largely of Asian breeds such as the Lhasa Apso, Shar Pei, and Akita. Group 2 is the mastiff group and includes, for example, the Boxer, Bull Dog, and Presa Canario. Group 4 includes a mixture of dogs including working breeds. Group 4 is enriched for sight and scent hounds and includes breeds such as the spaniels and retrievers well as gray wolves. Cluster 2 is typified by mastiff-type dogs with big, boxy heads and strong, sturdy bodies such as the Boxer, Mastiff, and Bulldog. The third and fourth clusters split a group of herding dogs and sight hounds away from the general population of modern hunting dogs comprised of terriers, hounds, and gun dog breeds. Ongoing studies are underway to expand this work to include more breeds. It is expected that this should allow even higher resolution of the breed relationships picture, and a clearer understanding of how to best combine data across breeds for fine resolution mapping studies.

4 Advances in Canine Genomics

While canine genetics has demonstrated significant progress in the past few years, the rate at which we can expect new discoveries will accelerate dramatically in the coming months. This is due almost exclusively to two major advances. First, the publication of a gene dense canine radiation hybrid (RH) map allowed us, for the first time, to understand the evolutionary relationship between the canine and the human genomes (Hitte et al., 2005). In this study, a well-spaced set of 9850 sequence tagged sites (STS) corresponding to a set of evenly spaced human genes selected from the then available x 1.5 poodle sequence (Kirkness et al., 2003) were localized on an RH map using a 9000 rad panel. Mutual-Blast alignments identified the best target (human) gene sequence using the dog sequence as a probe to ensure that we were, in fact, mapping the canine ortholog. A total of 9850 gene fragments were eventually mapped, which corresponds to approximately half of the genes in the dog genome, identifying some 264 conserved segments (CS) between dog and human.

Interestingly, most of these fragments (243) were later identified by the whole genome assembly (CanFam1.0) of the dog (Lindblad-Toh et al., 2005), generated from the x7.5 sequencing effort. This suggests that a dense RH map provides as much information for comparative genome mapping studies as a x7-10 whole genome shotgun sequence. In addition, detailed comparison of the canine x7.5 whole genome assembly (CanFam 1.0) to the 9000 rad RH map showed that 99.3% of the chromosomal assignments predicted by the RH map were in complete agreement with the sequence assembly. Those that were not were quickly resolved and found to represent issues such as the orientation of internal chromosomal fragments. This advance was critical in allowing scientists to move between the canine and the human maps, in assembling the canine genome sequence, and in finding the precise breakpoints between the canine and the human genomes (Murphy et al., 2005).

In addition to the above, the availability of both a x 1.5 poodle survey sequence and a whole genome assembly of a x7.5 boxer sequence is sure to impact canine genetics research at every level (Kirkness et al., 2003; Lindblad-Toh et al., 2005). We now know that the dog euchromatic genome is approximately 2.4 billion bases and is comprised of about 243 conserved segments when compared to the human genome. The assembled sequence is estimated to cover 98-99% of the genome, with the majority of the sequence contained within two supercontigs per chromosome. That is, on average, two segments of continuous sequence cover each of the dogs' 38 autosomes. The gene count, at ~19, 000, is less than what has been predicted for the human genome, perhaps due to complexities associated with splicing and gene families. There is a 1-1-1 correspondence between orthologs of human, mouse, and dog for 75% of the genes. The full genome sequence can be accessed through http://www.genome.ucsc.edu; http://www.ncbi.nih.gov, and http://www.ensembl.org. A discussion of mining the canine genome sequence is reviewed in O'Rourke (2005).

In addition to the Boxer sequence, a x 1.5 partial sequence of the Standard Poodle is available (Kirkness et al., 2003). While in itself less complete than the Boxer sequence, together these two resources have enabled the identification of more than 2 million single nucleotide polymorphisms (SNPs). We now know that a SNP occurs about once in every 1000 bases in dogs (Lindblad-Toh et al., 2005) and a first generation canine SNP chip is now available from Affymetrix. The chip contains some 24,000 working SNPs that will change the landscape of whole genome association studies in the dog. While microsatellites have proven sufficient for mapping single gene traits, it has generally not been possible to analyze enough markers to fully interrogate the genome in a complex trait association study. With thousands of SNPs available on a single chip, we believe that it is now possible to identify subtle variants responsible for a host of phenotypic observations.

Key to the development of the canine SNP chip were studies by both Lindblad-Toh et al. (Lindblad-Toh et al., 2005) and Sutter et al. (Sutter et al., 2004) who addressed the issue of how many SNPs are "enough" for doing whole genome association studies in the dog. Sutter and colleagues examined the extent of LD in five breeds with distinct breed histories and reported that the average length of LD in these five breeds is approximately 2 Mb (Fig. 3). This is 40-100 times further

Divergent Population Histories

Fig. 3 Divergent population histories of dog breeds. Breeds were selected by Sutter et al. (2004) in their study of linkage disequilibrium in dogs. Breeds were chosen to represent a variety of morphologic types, levels of present-day and historical popularity, population structure, and history (Wilcox and Walkowicz, 1995)

Bernese Mountain Dog - Small population today, severe population bottlenecks during world wars

Akita - Small population today, mixture ol isolated U.S. and Japanese populations. U.S. population bottleneck during world wars

Pekingese - Popular today, but few founders to U.S.

Labrador Retriever - Popular the past century

ยป^l Golden Retriever - Popular the past century.

Created 1800s from Tweed Water Spaniel, Yellow Retriever, Irish Setter, Bloodhound, circus dogs than the LD that typically extends in the human genome (Fig. 4). Thus, while a typical whole genome association study in humans requires about 500,000 SNPs (Kruglyak, 1999), in dogs the same study would require only about 10,000-30,000 markers. For diseases of interest to both human and canine health such as cancer, heart disease, cataracts, etc., these LD findings argue that it will be far easier to do the initial mapping study in dogs than in humans. These investigators also found that the extent of LD varied over a near 10-fold range between breeds of dog (0.43.2 Mb) (Sutter et al., 2004), arguing that breed selection would be important for the initial mapping of any trait of interest.

As part of the canine genome sequencing effort, Lindblad-Toh and colleagues undertook more extensive studies on canine LD, looking at more loci and more SNPs. They concluded that perhaps as few as 10,000 SNPs would be needed to fully cover the genome. They also found that the level of LD between breeds was different, but argued that the levels across the genome will likely vary more than the levels associated, on average, with any one dog breed versus another. Finally, both studies looked at the issue of haplotype sharing and demonstrated that there was low haplotype diversity and high haplotype sharing. Importantly, this means that a single set of SNPs, or a single SNP chip, is likely sufficient for mapping studies in any dog breed.

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