A Simple Genetic Architecture Underlies Morphological Variation in Dogs

Boyko, Adam R.; Quignon, Pascale; Lin, Liu; Schoenebeck, Jeffrey J.; Degenhardt, Jeremiah D.; Lohmueller, Kirk E.; Zhao, Keyan; Brisbin, Abra; Parker, Heidi G.; vonHoldt, Bridgett M.; Cargill, Michele; Auton, Adam; Reynolds, Andy; Elkahloun, Abdel G.; Castelhano, Marta G.; Mosher, Dana S.; Sutter, Nathan B.; Johnson, Gary S.; Novembre, John; Hubisz, Melissa J.; Siepel, Adam; Wayne, Robert K.; Bustamante, Carlos D.; Ostrander, Elaine A.

doi:10.1371/journal.pbio.1000451

Cited by 423 publications

(576 citation statements)

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“…Further, they assume positive selection that may increase the frequencies of many variants (i.e., polygenic selection) does not account for these patterns (6). However, polygenic selection does not appear to be the dominant force underlying phenotypic change in dogs, because association studies suggest that a small number of largeeffect alleles that have been subjected to artificial selection can account for much of the variance in traits (30,35,36). Finally, after filtering previously identified selective sweep regions, both the number of derived deleterious alleles and GERP score load remains significantly higher in dogs than wolves (P < 0.008), arguing that the genome-wide patterns are not driven by the artificially selected regions (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

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

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2-3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.M any of the mutations that arise in genomes are weakly deleterious and reduce fitness but are not always eliminated from the population by purifying natural selection. Consequently, understanding the reasons why deleterious mutations persist in populations and the role of demographic history in this process is of considerable interest (1-9). The radiation of domestic dogs offers a unique opportunity to address these questions. Dogs were originally domesticated from ancestral gray wolf populations >15,000 y ago in a process involving one or more severe population bottlenecks (10-12). The more recent isolation of modern dog breeds, which occurred over the last 300 y, involved additional population bottlenecks, intense artificial selection, and inbreeding Fig. 1A). Although this history is predicted to have resulted in the accumulation of deleterious variants, its specific effect on genomewide patterns of deleterious variation remains unclear.Here, we use complete genome sequencing data from 46 dogs representing 34 breeds, 25 village dogs, and 19 wolves to directly examine patterns of deleterious genetic variation across the dog genome (Dataset S1). Because more than half of these data derive from our own sequencing efforts, this project represents the largest survey of dog...

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Section: Significancementioning

confidence: 99%

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

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This study utilized data derived from the CanMap project (Boyko et al, 2010;vonHoldt et al, 2010) that provided genome-wide SNP data from 912 domestic dogs and 337 wild canids, based on genotyping with an Affymetrix Canine SNP Genome Mapping Array (coordinates based on the CanFam2 assembly). Samples were genotyped at 60 584 high-quality autosomal SNPs (referred to as 61K) and 851 X chromosome SNP loci (Boyko et al, 2010;vonHoldt et al, 2010).…”

Section: Data Setmentioning

confidence: 99%

“…Samples were genotyped at 60 584 high-quality autosomal SNPs (referred to as 61K) and 851 X chromosome SNP loci (Boyko et al, 2010;vonHoldt et al, 2010). Here, we used a subset of the CanMap SNP data set that consisted of 103 grey wolves: 54 from Eastern Europe, 19 from Italy, 6 from the Iberian Peninsula, 7 from Asia and 17 from North America, plus 5 coyotes that served as an outgroup (see Supplementary Table 1).…”

Section: Data Setmentioning

confidence: 99%

“…Long ROHs (41 Mb) are indicative of autozygosity (that is, homozygosity by descent) and are a product of recent demographic events such as inbreeding or admixture, whereas ROHs across shorter chromosome fragments (o1 Mb) are indicative of more ancient population processes (Boyko et al, 2010). As our goal was to find ROHs that represent autozygosity rather than simply occur by chance, this analysis was performed using the SNPs pruned for local LD (r 2 o0.5).…”

Section: Heterozygosity Linkage Disequilibrium and Autozygosity Analmentioning

confidence: 99%

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Genome-wide signatures of population bottlenecks and diversifying selection in European wolves

et al. 2013

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Genomic resources developed for domesticated species provide powerful tools for studying the evolutionary history of their wild relatives. Here we use 61K single-nucleotide polymorphisms (SNPs) evenly spaced throughout the canine nuclear genome to analyse evolutionary relationships among the three largest European populations of grey wolves in comparison with other populations worldwide, and investigate genome-wide effects of demographic bottlenecks and signatures of selection. European wolves have a discontinuous range, with large and connected populations in Eastern Europe and relatively smaller, isolated populations in Italy and the Iberian Peninsula. Our results suggest a continuous decline in wolf numbers in Europe since the Late Pleistocene, and long-term isolation and bottlenecks in the Italian and Iberian populations following their divergence from the Eastern European population. The Italian and Iberian populations have low genetic variability and high linkage disequilibrium, but relatively few autozygous segments across the genome. This last characteristic clearly distinguishes them from populations that underwent recent drastic demographic declines or founder events, and implies long-term bottlenecks in these two populations. Although genetic drift due to spatial isolation and bottlenecks seems to be a major evolutionary force diversifying the European populations, we detected 35 loci that are putatively under diversifying selection. Two of these loci flank the canine platelet-derived growth factor gene, which affects bone growth and may influence differences in body size between wolf populations. This study demonstrates the power of population genomics for identifying genetic signals of demographic bottlenecks and detecting signatures of directional selection in bottlenecked populations, despite their low background variability.

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“…The LUPA database, already containing genotypes from 10,000 dogs, can be used to perform GWAS across breeds, with the aim to identify variants underlying traits shared by several breeds, as has already been documented in other studies (Jones et al, 2008;Cadieu et al, 2009;Akey et al, 2010;Bannasch et al, 2010;Boyko et al, 2010). An alternative approach searches for selective sweeps: regions with reduced heterozygosity associated with a specific trait within a single or within a group of breeds that share the same trait (A. Vaysse personal communication).…”

Section: Detecting Signatures Of Selectionmentioning

confidence: 99%

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

Lequarré

Andersson

André

et al. 2011

The Veterinary Journal

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a b s t r a c tThe domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.

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A Simple Genetic Architecture Underlies Morphological Variation in Dogs

Abstract: The largest genetic study to date of morphology in domestic dogs identifies genes controlling nearly 100 morphological traits and identifies important trends in phenotypic variation within this species.

Cited by 423 publications

References 50 publications

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

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

Genome-wide signatures of population bottlenecks and diversifying selection in European wolves

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

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