Derived variants at six genes explain nearly half of size reduction in dog breeds

Abstract

Selective breeding of dogs by humans has generated extraordinary diversity in body size. A number of multibreed analyses have been undertaken to identify the genetic basis of this diversity. We analyzed four loci discovered in a previous genome-wide association study that used 60,968 SNPs to identify size-associated genomic intervals, which were too large to assign causative roles to genes. First, we performed fine-mapping to define critical intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2, identifying five highly associated markers at the four loci. We hypothesize that three of the variants are likely to be causative. We then genotyped each marker, together with previously reported size-associated variants in the IGF1 and IGF1R genes, on a panel of 500 domestic dogs from 93 breeds, and identified the ancestral allele by genotyping the same markers on 30 wild canids. We observed that the derived alleles at all markers correlated with reduced body size, and smaller dogs are more likely to carry derived alleles at multiple markers. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. Finally, we show that 46%-52.5% of the variance in body size of dog breeds can be explained by seven markers in proximity to exceptional candidate genes. Among breeds with standard weights <41 kg (90 lb), the genotypes accounted for 64.3% of variance in weight. This work advances our understanding of mammalian growth by describing genetic contributions to canine size determination in non-giant dog breeds.

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

“…These regions varied largely in size (750,000-6,250,000 bp, median 1,500,000 bp), and contained 646 genes in total. Within the most differentiated regions we noticed several genes previously associated with size or skeletal features in other species including LCORL-NCAPG (e.g., Gudbjartsson et al 2008;Rubin et al 2012;Tetens et al 2013;Sahana et al 2015), STC2 (Gagliardi et al 2005;Rimbault et al 2013), HOXD cluster (Zakany and Duboule 2007), COL11A1 (Li et al 1995;Annunen et al 1999), and IGF2BP2 (Dai et al 2015) (Figure 4A). …”

Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis

“…Similar findings have recently resulted from genetic studies of domestic dogs, which show the greatest variation in body size of any land mammal (45). It was found that the occurrence of derived variants at only six genes is a major explanation for the extreme reduction in body size of dogs caused by selective breeding (46). The authors found STC2 to be among the genes, also including IGF1 and IGF1R.…”

Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness

“…We initially identified two loci on the X chromosome spanning several megabases (Mb) as contributors to body size in large breeds through a GWAS of 915 dogs representing 80 domestic dog breeds [22]. The result has since been replicated by several groups [22,23,47,48]. No study, however has explored the result in detail, in part because the lack of heterozygosity on the canine X chromosome can reflect popular sire effects, which may complicate fine mapping efforts.…”