Comparative Mammalian Genomics

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Canine Genetics Canine Origins Our canine studies are divided into genomics of domestication, morphologic variation, and disease gene mapping. With regard to the first we have published recent, high-profile papers that describe the domestication of dogs (vonHoldt et al., 2013). This builds on previous work, published in Nature, where we presented a refined description of how breeds are related to each other (vonHoldt et al., 2010). Very recently, in a collaboration led by Dr. John Novembre at UCLA, sequencing of wild canids revealed a severe 30-fold reduction in effective population size that likely occurred during the domestication bottleneck, which we now estimate occurred about 15,000 years ago (Freedman, 2014). These data also show that none of the extant wolf lineages from putative domestication centers are directly ancestral to dogs, implying that a now extinct population of wolves may be the missing link in dog evolution. Finally, the study demonstrates selection on genes affecting brain function, metabolism, and morphology, supporting a major role for regulatory evolution in domestication. We also show evidence for hybridization between dogs and wolves, and provide a tool kit with population-level statistical quantification that can detect recent dog-wolf hybridization using a panel of dog-wolf ancestry-informative SNPs with divergent allele frequency distributions (VonHoldt et al., 2013). Morphology A majority of our dog papers over the past four years reveal our growing understanding of canine genome organization and its relationship to morphologic variation between breeds. Our newest avenue of morphologic study is aimed at understanding the genetic underpinning of skull shape variation (Schoenebeck, 2014) which varies dramatically across breeds (Schoenebeck, 2013; Schoenebeck et al., 2012). To quantify the variation, we collected data from 533 museum skulls at 51 landmarks using a microscribe digitizer. The resulting principal components analysis (PCA) showed that the top four PCs account for about 77% of skull variance across breeds. PC1 describes profound changes in rostrum length and angle, palate and zygomatic arch width, and depth of the neurocranium; essentially the continuum of craniofacial features that extend between brachycephalic (short head like a bulldog) and dolichocephalic (long head like a greyhound) skulls. Our GWAS on PC1 revealed several loci. The CFA32 locus demonstrated a marked reduction in observed heterozygosity (Ho) and elevated genetic differentiation (FST), which are hallmarks of strong selection. We identified causative variants on CFA32 but whole genome sequence from 12 dog breeds of widely varying skull shapes allowed us to reduce it to one, an F452L missense mutation in the bone morphogenesis protein 3 (BMP3) gene (BMP3F452L). We also expanded our body size studies (Rimbault, 2013). In this paper we analyzed four loci discovered in a previous genome-wide association study to define small intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2. 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. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. 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 at least 64.3% of variance in weight. This work helps to advance our understanding of canine body size and body size genetics for mammals in general. Finally we did work on canine coat color, showing that a multi-gene interaction involving ASIP, RALY, MC1R, DEFB103, and a yet-unidentified modifier gene is required for expression of saddle tan color pattern (Dreger et al, 2013). Canine Cancer The tremendous phenotypic diversity of modern dog breeds represents the end point of a >15,000-year experiment in artificial and natural selection. Each breed has undergone strong artificial selection, in which dog fanciers selected for many traits including body size, fur type, color, skull shape, and even behavior, to create novel breeds. The adoption of the breed barrier rule that no dog may become a registered member of a breed unless both its dam and sire are registered members ensures a relatively closed genetic pool within each breed. As a result, there is strong phenotypic homogeneity within the breeds recognized including breed-associated genetic disease. Our recent genetic studies of dog disease have focused almost exclusively on cancer, which we argue is a strong model for human cancer genetics. Squamous cell carcinoma of the digit (SCCD) is a locally aggressive cancer typified by lytic bone lesions, recurrence, and occasional death from metastasis. Standard Poodles are among the breeds with the highest risk of SCCD, however only the dark pigmented standard poodles are susceptible. We conducted a GWAS using on black Standard Poodles, and demonstrated that the Kit Ligand (KITLG) locus is strongly associated with SCCD. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 10(-8)) (Karyadi 2013). Dogs without at least one allele with four copies in cis are not at any risk for disease (Karyadi, 2013). This locus is under strong selective pressure in dogs, likely in response to coat color preferences, as KITLG has been linked to pigmentation in humans, mice and fish.