Breed relationships facilitate fine-mapping studies: A 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds

Abstract

The features of modern dog breeds that increase the ease of mapping common diseases, such as reduced heterogeneity and extensive linkage disequilibrium, may also increase the difficulty associated with fine mapping and identifying causative mutations. One way to address this problem is by combining data from multiple breeds segregating the same trait after initial linkage has been determined. The multibreed approach increases the number of potentially informative recombination events and reduces the size of the critical haplotype by taking advantage of shortened linkage disequilibrium distances found across breeds. In order to identify breeds that likely share a trait inherited from the same ancestral source, we have used cluster analysis to divide 132 breeds of dog into five primary breed groups. We then use the multibreed approach to fine-map Collie eye anomaly (cea), a complex disorder of ocular development that was initially mapped to a 3.9-cM region on canine chromosome 37. Combined genotypes from affected individuals from four breeds of a single breed group significantly narrowed the candidate gene region to a 103-kb interval spanning only four genes. Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind. This work both establishes that the primary cea mutation arose as a single disease allele in a common ancestor of herding breeds as well as highlights the value of comparative population analysis for refining regions of linkage.

Genetic characterization of four native Italian shepherd dog breeds and analysis of their relationship to cosmopolitan dog breeds using microsatellite markers

“…MSD and BCO have different origins, are quite different morphologically and are also utilized for different purposes, as the MSD is a guard dog and the BCO is a herding dog. However this unexpected finding is in agreement with the results of another study (Parker et al, 2007), that considered 132 different dog breeds, where the Border Collie clustered together with the Kuvasz. This last breed is a Hungarian dog, that is similar to the Maremma Sheepdog, it is utilized for the same purpose and may have a common ancestor, together with other European dogs, like Tatra from Poland, Sarplaninac from the Balkans and the Pyrenean Mountain Dog (Breber, 1990).…”

Mapping DNA structural variation in dogs

“…Genotyping of polymorphic canine loci has confirmed that most breeds cluster into breed classes (Parker et al , 2007. To survey CNV in normal pedigreed dogs, we assayed nine dogs that represent four main breed classes-Asian/ancient, Mastiff, Herding, and Hunting (Table 1A; Parker et al 2004).…”

“…The phylogenetic tree of that data only resolved three high confidence branches-wolf, ancient/Asian dogs, and all other dogs. However, they ascertained genetic relationships to different degrees of confidence (very high to low) using Bayesian model-based clustering (Parker et al , 2007. Those studies suggested it might be difficult to solve the phylogeny of dogs due to the admixture of breeds.…”

“…For example, the first genetic grouping of breeds was consistent with the historical designation of a single Mastiff class that includes subclasses of Mastiffs, Draft/Cattle dogs, and Bulldogs ). More recently, it was proposed that Mastiffs and Bulldogs (including many terriers) group together and Draft/Cattle dogs (including mountain dogs) form another group (Parker et al 2007). Our clustering findings hint that higher density CNV information may yield a phylogenetic tree of dog breeds.…”

“…In other words, while broad mapping is accelerated using single breeds, fine mapping can be done in related breeds. This power has begun to be applied with success Parker et al 2007;Sutter et al 2007). The unique genetic history of dogs thus makes them an ideal mammal in which to study the biology of CNV.…”