Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

Abstract

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

“…LCORL-NCAPG are, together with HMGA2, two of the loci that are most consistently associated with stature and body size variation across multiple studies and species. The LCORL-NCAP region has previously been associated with body size in human, cattle, dog, pig, and horse (Gudbjartsson et al 2008;Pryce et al 2011;Vaysse et al 2011;Rubin et al 2012;Signer-Hasler et al 2012;Tetens et al 2013;Sahana et al 2015). Our results are consistent with a selective sweep at the LCORL-NCAP region related to selection for increased size in domestic rabbits, since all normal-sized rabbits included in this study are significantly larger than wild rabbits and were fixed for a single haplotype ( Figure 4B).…”

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

“…To increase statistical power, we repeated our analyses by using 2,535 genes causing Mendelian diseases in humans based on the shared disease etiology between humans and dogs (46,47). We find more Mendelian disease genes overlap with genes near the selective sweeps reported by Vaysse et al (44) and Akey et al (45) (i.e., sweeps related to breed formation) than expected by chance (P = 0.005 and P = 0.057, respectively; SI Appendix, Table S9). This enrichment could be explained by two different mechanisms.…”

“…We assessed whether artificial selection may partially be responsible for the numerous Mendelian genetic diseases observed in breed dogs. Specifically, we determined whether the previously reported targets of selective sweeps (12,42,44,45) were enriched for genes implicated in disease. We find slightly more overlap among 145 genes implicated in Mendelian disease in dogs and genes near recent selective sweeps than expected by chance (P = 0.087 and P = 0.155; SI Appendix, Table S8).…”

Porcine colonization of the Americas: a 60k SNP story

“…Some environments like high altitude in the altiplano or extreme and continuous heat in Cuba or North East Brazil also poses serious physiological challenges. The fact that adaptation must have occurred in a short time span suggests that rapid changes in allelic frequencies must have occurred, and also that excess of differentiation (for example, F ST ) can be a good proxy to detect these events (Akey et al, 2002;Vaysse et al, 2012).…”