Extensive and breed-specific linkage disequilibrium in Canis familiaris

Abstract

The 156 breeds of registered dogs in the United States offer a unique opportunity to map genes important in disease susceptibility, morphology, and behavior. Linkage disequilibrium (LD) is of current interest for its application in whole genome association mapping, since the extent of LD determines the feasibility of such studies. We have measured LD at five genomic intervals, each 5 Mb in length and composed of five clusters of sequence variants spaced 800 kb-1.6 Mb apart. These intervals are located on canine chromosomes 1, 2, 3, 34, and 37, and none is under obvious selective pressure. Approximately 20 unrelated dogs were assayed from each of five breeds: Akita, Bernese Mountain Dog, Golden Retriever, Labrador Retriever, and Pekingese. At each genomic interval, SNPs and indels were discovered and typed by resequencing. Strikingly, LD in canines is much more extensive than in humans: D' falls to 0.5 at 400-700 kb in Golden Retriever and Labrador Retriever, 2.4 Mb in Akita, and 3-3.2 Mb in Bernese Mountain Dog and Pekingese. LD in dog breeds is up to 100x more extensive than in humans, suggesting that a correspondingly smaller number of markers will be required for association mapping studies in dogs compared to humans. We also report low haplotype diversity within regions of high LD, with 80% of chromosomes in a breed carrying two to four haplotypes, as well as a high degree of haplotype sharing among breeds.

Figure 1.

Schematic design of resequencing strategy for each of five loci, one each on canine chromosomes 1, 2, 3, 34, and 37. At each locus sequence reads were clustered into five “regions.” Each region is composed of one to five sequence reads (average, 2.8). Regions are separated by ∼0.8 or ∼1.6 Mb.

Figure 2.

(A) Triangle plots of LD between common SNPs (MAF > 0.2) for each chromosome and dog breed. Black squares represent SNP pairs in significant LD (D′ > 0.8; P < 0.01) and <100 kb apart. Red squares indicate significant LD between markers at least 0.8 Mb apart. Gray squares represent high LD values (D′ > 0.8) that are less significant (P > 0.01). (B) LD (D′) decay plots for common SNPs (MAF > 0.2) in each dog breed corresponding to the triangle plots above. Red circles show the median LD values within each bin of marker pair distances, and the dashed line is a best-fitting curve to the median values. Gray shading indicates the background LD level between unlinked markers. The top of the gray rectangle shows the median of D′ values between markers on different chromosomes.

Figure 3.

Relationship between the number of markers and the number of haplotypes observed for 10 regions selected for haplotype analysis. This count of haplotypes is the average over the five breeds for the number of haplotypes carried by 80% of chromosomes within the breed. Two regions with four markers have the same average number of haplotypes as regions with more markers.