Demographic history, selection and functional diversity of the canine genome

The domestic dog represents one of the most dramatic long-term evolutionary experiments undertaken by humans. From a large wolf-like progenitor, unparalleled diversity in phenotype and behaviour has developed in dogs, providing a model for understanding the developmental and genomic mechanisms of diversification. We discuss pattern and process in domestication, beginning with general findings about early domestication and problems in documenting selection at the genomic level. Furthermore, we summarize genotype–phenotype studies based first on single nucleotide polymorphism (SNP) genotyping and then with whole-genome data and show how an understanding of evolution informs topics as different as human history, adaptive and deleterious variation, morphological development, ageing, cancer and behaviour.

[1]  A. Oberbauer,et al.  Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). , 2013, Journal of the American Veterinary Medical Association.

[2]  R. Wayne CRANIAL MORPHOLOGY OF DOMESTIC AND WILD CANIDS: THE INFLUENCE OF DEVELOPMENT ON MORPHOLOGICAL CHANGE , 1986, Evolution; international journal of organic evolution.

[3]  Holly C. Beale,et al.  Variation of BMP3 Contributes to Dog Breed Skull Diversity , 2012, PLoS genetics.

[4]  E. Murchison,et al.  The changing global distribution and prevalence of canine transmissible venereal tumour , 2014, BMC Veterinary Research.

[5]  K. Overall Natural animal models of human psychiatric conditions: assessment of mechanism and validity , 2000, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[6]  K. Abe,et al.  Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1 , 2015, Hormone Research in Paediatrics.

[7]  E. Ostrander,et al.  "Lassie," "Toto," and fellow pet dogs: poised to lead the way for advances in cancer prevention. , 2015, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[8]  Sara E. Kalla,et al.  Complex disease and phenotype mapping in the domestic dog , 2016, Nature Communications.

[9]  James A. Cuff,et al.  Genome sequence, comparative analysis and haplotype structure of the domestic dog , 2005, Nature.

[10]  E. Ostrander,et al.  Transmissible Tumors: Breaking the Cancer Paradigm. , 2016, Trends in genetics : TIG.

[11]  Jeffrey D. Jensen,et al.  The impact of equilibrium assumptions on tests of selection , 2013, Front. Genet..

[12]  Keith Dobney,et al.  Genomic and archaeological evidence suggest a dual origin of domestic dogs , 2016, Science.

[13]  R. Wayne,et al.  Deciphering the Origin of Dogs: From Fossils to Genomes. , 2017, Annual review of animal biosciences.

[14]  E. Ostrander,et al.  Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes , 2008, Genetics.

[15]  C. E. Alvarez,et al.  Dog models of naturally occurring cancer. , 2011, Trends in molecular medicine.

[16]  C. Bustamante,et al.  Molecular and Evolutionary History of Melanism in North American Gray Wolves , 2009, Science.

[17]  Catherine André,et al.  Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes , 2009, Science.

[18]  Love Dalén,et al.  Ancient Wolf Genome Reveals an Early Divergence of Domestic Dog Ancestors and Admixture into High-Latitude Breeds , 2015, Current Biology.

[19]  D. Givol,et al.  Common origin of transmissible venereal tumors (TVT) in dogs. , 1987, Oncogene.

[20]  Christian Peter Klingenberg,et al.  Large‐Scale Diversification of Skull Shape in Domestic Dogs: Disparity and Modularity , 2010, The American Naturalist.

[21]  Peter J. Campbell,et al.  Transmissible Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage , 2014, Science.

[22]  K. Svenson,et al.  Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2 , 2017, Current Biology.

[23]  A. Boyko The domestic dog: man's best friend in the genomic era , 2011, Genome Biology.

[24]  Xiang Gao,et al.  Generation of gene-target dogs using CRISPR/Cas9 system. , 2015, Journal of molecular cell biology.

[25]  E. Ostrander,et al.  Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness , 2017, PLoS genetics.

[26]  G. Mauldin,et al.  Canine histiocytic neoplasia: an overview. , 2007, The Canadian veterinary journal = La revue veterinaire canadienne.

[27]  K. Lindblad-Toh,et al.  Efficient mapping of mendelian traits in dogs through genome-wide association , 2007, Nature Genetics.

[28]  Robin A. Weiss,et al.  Clonal Origin and Evolution of a Transmissible Cancer , 2006, Cell.

[29]  K. Melkersson,et al.  P-709 - Association Between Body Mass Index and Insulin Receptor Substrate-4 (irs-4) Gene Polymorphisms in Patients With Schizophrenia , 2012, European Psychiatry.

[30]  N. Dodman,et al.  Description and development of compulsive tail chasing in terriers and response to clomipramine treatment. , 1998, Journal of the American Veterinary Medical Association.

[31]  E. Ostrander,et al.  The Genetics of Canine Skull Shape Variation , 2013, Genetics.

[32]  Ilan Gronau,et al.  Genome Sequencing Highlights the Dynamic Early History of Dogs , 2014, PLoS genetics.

[33]  T. Marquès-Bonet,et al.  Worldwide patterns of genomic variation and admixture in gray wolves , 2016, Genome research.

[34]  Carlos D Bustamante,et al.  Genetic structure in village dogs reveals a Central Asian domestication origin , 2015, Proceedings of the National Academy of Sciences.

[35]  L. van den Berg,et al.  Behavior Genetics of Canine Aggression: Behavioral Phenotyping of Golden Retrievers by Means of an Aggression Test , 2003, Behavior genetics.

[36]  K. Lindblad-Toh,et al.  The dog as a cancer model , 2006, Nature Biotechnology.

[37]  D. Palmer,et al.  An Age-Associated Decline in Thymic Output Differs in Dog Breeds According to Their Longevity , 2016, PloS one.

[38]  Zhi-Bin Yu,et al.  Cardiac Troponin T Variants Produced by Aberrant Splicing of Multiple Exons in Animals with High Instances of Dilated Cardiomyopathy* , 2002, The Journal of Biological Chemistry.

[39]  S. Sawyer,et al.  Complete Mitochondrial Genomes of Ancient Canids Suggest a European Origin of Domestic Dogs , 2013, Science.

[40]  J. Doudna,et al.  A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity , 2012, Science.

[41]  Joseph A DiMasi,et al.  Economics of new oncology drug development. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  D. Nussey,et al.  Ageing: It’s a Dog’s Life , 2013, Current Biology.

[43]  E. Ostrander,et al.  Whole-genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic-trait mapping , 2016, Disease Models & Mechanisms.

[44]  Clive D. L. Wynne,et al.  Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs , 2017, Science Advances.

[45]  Jeremiah D. Degenhardt,et al.  A Simple Genetic Architecture Underlies Morphological Variation in Dogs , 2010, PLoS biology.

[46]  Rodolphe Barrangou,et al.  Diversity of CRISPR-Cas immune systems and molecular machines , 2015, Genome Biology.

[47]  Ilan Gronau,et al.  Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs , 2016, PLoS genetics.

[48]  T. Derrien,et al.  A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies , 2016, PLoS genetics.

[49]  J. Rapoport,et al.  Drug treatment of canine acral lick. An animal model of obsessive-compulsive disorder. , 1992, Archives of general psychiatry.

[50]  T. Kikusui,et al.  Copy number variations in the amylase gene (AMY2B) in Japanese native dog breeds. , 2015, Animal genetics.

[51]  Jacob A. Tennessen,et al.  Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes , 2012, Science.

[52]  E. Ostrander,et al.  Canine Morphology: Hunting for Genes and Tracking Mutations , 2010, PLoS biology.

[53]  L. Goodloe,et al.  Companion dog temperament traits. , 1998, Journal of applied animal welfare science : JAAWS.

[54]  T. Ohta Role of very slightly deleterious mutations in molecular evolution and polymorphism. , 1976, Theoretical population biology.

[55]  E. Ostrander,et al.  Genomic Analyses Reveal the Influence of Geographic Origin, Migration, and Hybridization on Modern Dog Breed Development. , 2017, Cell reports.

[56]  M. Neff,et al.  A Fetching Model Organism , 2006, Cell.

[57]  Å. Hedhammar,et al.  Mortality in over 350,000 Insured Swedish dogs from 1995–2000: I. Breed-, Gender-, Age- and Cause-specific Rates , 2005, Acta veterinaria Scandinavica.

[58]  C. Dorn Epidemiology of canine and feline tumors [Dogs, cats]. , 1976 .

[59]  K. Lindblad-Toh,et al.  Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping , 2011, PLoS genetics.

[60]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[61]  E. Kirkness,et al.  Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. , 2007, Genome research.

[62]  Jeremiah D. Degenhardt,et al.  Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication , 2010, Nature.

[63]  R. Mägi,et al.  Selective sweep on human amylase genes postdates the split with Neanderthals , 2016, Scientific Reports.

[64]  U. Pettersson,et al.  The genetic contribution to canine personality , 2006, Genes, brain, and behavior.

[65]  P. Moore,et al.  Canine Hemophagocytic Histiocytic Sarcoma: A Proliferative Disorder of CD11d+ Macrophages , 2006, Veterinary pathology.

[66]  K. Lindblad-Toh,et al.  Localization of Canine Brachycephaly Using an Across Breed Mapping Approach , 2010, PloS one.

[67]  A. Cagan,et al.  Identification of genomic variants putatively targeted by selection during dog domestication , 2016, BMC Evolutionary Biology.

[68]  N. Toft,et al.  Cognitive Function, Progression of Age‐related Behavioral Changes, Biomarkers, and Survival in Dogs More Than 8 Years Old , 2015, Journal of veterinary internal medicine.

[69]  E. Ostrander,et al.  The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs , 2012, Mammalian Genome.

[70]  J. Dobson Breed-Predispositions to Cancer in Pedigree Dogs , 2013, ISRN veterinary science.

[71]  Thomas J. Nicholas,et al.  Tracking footprints of artificial selection in the dog genome , 2010, Proceedings of the National Academy of Sciences.

[72]  T. Capellini,et al.  Dietary Variation and Evolution of Gene Copy Number among Dog Breeds , 2016, PloS one.

[73]  K. Lindblad-Toh,et al.  A Simple Repeat Polymorphism in the MITF-M Promoter Is a Key Regulator of White Spotting in Dogs , 2014, PloS one.

[74]  E. Mauceli,et al.  A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs , 2011, PLoS genetics.

[75]  T. Jacobs,et al.  Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests , 2016, Journal of Alzheimer's disease : JAD.

[76]  Guo-Dong Wang,et al.  Out of southern East Asia: the natural history of domestic dogs across the world , 2015, Cell Research.

[77]  E. C. Ash Dogs: their History and Development , 1927, Nature.

[78]  Gary K. Chen,et al.  Correction: Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry , 2011, PLoS Genetics.

[79]  C. London,et al.  Dogs as a Model for Cancer. , 2016, Annual review of animal biosciences.

[80]  Israel Steinfeld,et al.  Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells , 2015, Nature Biotechnology.

[81]  N. Schork,et al.  An Assessment of the Individual and Collective Effects of Variants on Height Using Twins and a Developmentally Informative Study Design , 2011, PLoS genetics.

[82]  Matthew Oetjens,et al.  Ancient European dog genomes reveal continuity since the Early Neolithic , 2016, Nature Communications.

[83]  J. Wood,et al.  Methods and mortality results of a health survey of purebred dogs in the UK. , 2010, The Journal of small animal practice.

[84]  B. Craig,et al.  Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer , 2015, PloS one.

[85]  K. Lindblad-Toh,et al.  A canine chromosome 7 locus confers compulsive disorder susceptibility , 2010, Molecular Psychiatry.

[86]  L. Olohan,et al.  Copper toxicosis in non-COMMD1 Bedlington terriers is associated with metal transport gene ABCA12. , 2016, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[87]  Erik Axelsson,et al.  Amy2B copy number variation reveals starch diet adaptations in ancient European dogs , 2016, Royal Society Open Science.

[88]  Arie Johannes Van Der Spek,et al.  Cognitive disturbances in old dogs suffering from the canine counterpart of Alzheimer's disease , 2006, Brain Research.

[89]  N. Toft,et al.  An observational study with long-term follow-up of canine cognitive dysfunction: clinical characteristics, survival, and risk factors. , 2013, Journal of veterinary internal medicine.

[90]  N. Barton,et al.  Genetic hitchhiking. , 2000, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[91]  G. Waldemar,et al.  Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. , 2016, Journal of Alzheimer's disease : JAD.

[92]  E. Ostrander,et al.  Commonalities in Development of Pure Breeds and Population Isolates Revealed in the Genome of the Sardinian Fonni's Dog , 2016, Genetics.

[93]  Tomoko Ohta,et al.  Weak Selection and Protein Evolution , 2012, Genetics.

[94]  E. Ostrander,et al.  Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic. , 2009, The Journal of heredity.

[95]  Yixue Li,et al.  Genomic Analysis Reveals Hypoxia Adaptation in the Tibetan Mastiff by Introgression of the Gray Wolf from the Tibetan Plateau , 2016, Molecular biology and evolution.

[96]  Le Cong,et al.  Multiplex Genome Engineering Using CRISPR/Cas Systems , 2013, Science.

[97]  M. Feldman,et al.  The Italian genome reflects the history of Europe and the Mediterranean basin , 2015, European Journal of Human Genetics.

[98]  B. Fuchs,et al.  Comparative biology of human and canine osteosarcoma. , 2007, Anticancer research.

[99]  Claudio J. Verzilli,et al.  An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People , 2012, Science.

[100]  J. Serpell,et al.  Development and validation of a questionnaire for measuring behavior and temperament traits in pet dogs. , 2003, Journal of the American Veterinary Medical Association.

[101]  J. Wood,et al.  Mortality in a cohort of flat-coated retrievers in the UK. , 2009, Veterinary and comparative oncology.

[102]  N. Pedersen,et al.  The ascent of cat breeds: genetic evaluations of breeds and worldwide random-bred populations. , 2008, Genomics.

[103]  C. Bustamante,et al.  A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs , 2007, PLoS genetics.

[104]  P. Keightley,et al.  Joint Inference of the Distribution of Fitness Effects of Deleterious Mutations and Population Demography Based on Nucleotide Polymorphism Frequencies , 2007, Genetics.

[105]  L. Akslen,et al.  Frequency of somatic BRAF mutations in melanocytic lesions from patients in a CDK4 melanoma family , 2014, Pigment cell & melanoma research.

[106]  E. Kirkness,et al.  Extensive and breed-specific linkage disequilibrium in Canis familiaris. , 2004, Genome research.

[107]  M. Pugliese,et al.  Rapid improvement of canine cognitive dysfunction with immunotherapy designed for Alzheimer's disease. , 2013, Current Alzheimer research.

[108]  Chung-I Wu,et al.  Genetic Convergence in the Adaptation of Dogs and Humans to the High-Altitude Environment of the Tibetan Plateau , 2014, Genome biology and evolution.

[109]  E. Ostrander,et al.  Telomere length correlates with life span of dog breeds. , 2012, Cell reports.

[110]  A. Auton,et al.  Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder , 2014, Genome Biology.

[111]  M. Slatkin,et al.  Ancient DNA and human history , 2016, Proceedings of the National Academy of Sciences.

[112]  M. Rothschild,et al.  Evidence of selection signatures that shape the Persian cat breed , 2016, Mammalian Genome.

[113]  A. Paradiso,et al.  A model of study for human cancer: Spontaneous occurring tumors in dogs. Biological features and translation for new anticancer therapies. , 2013, Critical reviews in oncology/hematology.

[114]  Jeffrey C Phillips,et al.  A novel locus for canine osteosarcoma (OSA1) maps to CFA34, the canine orthologue of human 3q26. , 2010, Genomics.

[115]  A. Kubicka The Invaders. How Humans and Their Dogs Drove Neanderthals to Extinction , 2016 .

[116]  M. Slatkin,et al.  Genetic hitch-hiking in a subdivided population. , 1998, Genetical research.

[117]  E. Macewen,et al.  Spontaneously Occurring Tumors of Companion Animals as Models for Human Cancer , 2000, Cancer investigation.

[118]  H. Vries,et al.  Phenotyping of Aggressive Behavior in Golden Retriever Dogs with a Questionnaire , 2006, Behavior genetics.

[119]  M. Whiteley,et al.  Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs , 2011, PloS one.

[120]  P. Moore,et al.  Localized and Disseminated Histiocytic Sarcoma of Dendritic Cell Origin in Dogs , 2002, Veterinary pathology.

[121]  E. Ostrander,et al.  Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[122]  A. Boyko,et al.  Population variation revealed high-altitude adaptation of Tibetan mastiffs. , 2014, Molecular biology and evolution.

[123]  E. Ostrander,et al.  Canine behavioral genetics: pointing out the phenotypes and herding up the genes. , 2008, American journal of human genetics.

[124]  Lin Lin,et al.  CRISPR-mediated multiplexed genetic manipulation , 2016, Oncotarget.

[125]  C. E. Alvarez,et al.  Genetic mapping of canine fear and aggression , 2016, BMC Genomics.

[126]  E. Ostrander,et al.  Insights into morphology and disease from the dog genome project. , 2014, Annual review of cell and developmental biology.

[127]  Nicholas H. Barton,et al.  The effect of hitch-hiking on neutral genealogies , 1998 .

[128]  E. H. Margulies,et al.  An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs , 2009, Science.

[129]  D. Promislow,et al.  The Size–Life Span Trade-Off Decomposed: Why Large Dogs Die Young , 2013, The American Naturalist.

[130]  Ryan D. Hernandez,et al.  Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome , 2008, PLoS genetics.

[131]  E. Axelsson,et al.  Diet adaptation in dog reflects spread of prehistoric agriculture , 2016, Heredity.

[132]  M. Karas,et al.  Insulin Receptor Substrate-4 Enhances Insulin-like Growth Factor-I-induced Cell Proliferation* , 1999, The Journal of Biological Chemistry.

[133]  Z. Tümer,et al.  Association study between CDH2 and Gilles de la Tourette syndrome in a Danish cohort , 2015, Psychiatry Research.

[134]  N. Cottam,et al.  Blanket and flank sucking in Doberman Pinschers. , 2007, Journal of the American Veterinary Medical Association.

[135]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[136]  K. Lindblad-Toh,et al.  The genomic signature of dog domestication reveals adaptation to a starch-rich diet , 2013, Nature.

[137]  Elaine A. Ostrander,et al.  Canine Genetics Offers New Mechanisms for the Study of Human Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[138]  R. Wayne,et al.  EPAS1 variants in high altitude Tibetan wolves were selectively introgressed into highland dogs , 2017, PeerJ.

[139]  L. Dunkel,et al.  IGSF1 variants in boys with familial delayed puberty , 2014, European Journal of Pediatrics.

[140]  Holly C. Beale,et al.  Derived variants at six genes explain nearly half of size reduction in dog breeds , 2013, Genome research.

[141]  Yixue Li,et al.  Genomic Analysis Reveals Hypoxia Adaptation in the Tibetan Mastiff by Introgression of the Gray Wolf from the Tibetan Plateau. , 2016, Molecular biology and evolution.

[142]  Chaochun Wei,et al.  Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia , 2014, Genome research.

[143]  R. Gasser,et al.  Homozygosity mapping and sequencing identify two genes that might contribute to pointing behavior in hunting dogs , 2015, Canine Genetics and Epidemiology.

[144]  A. Caballero,et al.  Variation After a Selective Sweep in a Subdivided Population , 2005, Genetics.

[145]  E. Ostrander,et al.  A Copy Number Variant at the KITLG Locus Likely Confers Risk for Canine Squamous Cell Carcinoma of the Digit , 2013, PLoS genetics.

[146]  Shannon E. K. Joslin,et al.  A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats , 2013, Scientific Reports.

[147]  D. Zhao,et al.  Polymorphisms of the prion protein gene (PRNP) in the Tibetan Mastiff. , 2009, Animal genetics.

[148]  E. Ostrander Franklin H. Epstein Lecture. Both ends of the leash--the human links to good dogs with bad genes. , 2012, The New England journal of medicine.

[149]  R. Wayne,et al.  Limb morphology of domestic and wild canids: The influence of development on morphologic change , 1986, Journal of morphology.

[150]  F. Galibert,et al.  Chromosome aberrations in canine multicentric lymphomas detected with comparative genomic hybridisation and a panel of single locus probes , 2003, British Journal of Cancer.

[151]  Natalie,et al.  Genetic Structure of the Purebred Domestic Dog , 2004 .

[152]  E. Ostrander,et al.  Man's best friend becomes biology's best in show: genome analyses in the domestic dog. , 2010, Annual review of genetics.

[153]  E. Ostrander,et al.  Domestic dogs and cancer research: a breed-based genomics approach. , 2014, ILAR journal.

[154]  S. Čepica,et al.  Mapping of QTL on chromosome X for fat deposition, muscling and growth traits in a wild boar x Meishan F2 family using a high-density gene map. , 2007, Animal genetics.

[155]  D. Milan,et al.  Fine mapping of fatness QTL on porcine chromosome X and analyses of three positional candidate genes , 2013, BMC Genetics.

[156]  Jacqueline K. White,et al.  Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement , 2012, Nature Genetics.

[157]  T. Marquès-Bonet,et al.  Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs , 2015, Proceedings of the National Academy of Sciences.

[158]  G. Church,et al.  Cas9 as a versatile tool for engineering biology , 2013, Nature Methods.

[159]  M. Ceppi,et al.  Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. , 2008, Journal of veterinary internal medicine.

[160]  Jeremiah D. Degenhardt,et al.  Complex population structure in African village dogs and its implications for inferring dog domestication history , 2009, Proceedings of the National Academy of Sciences.

[161]  C. Bustamante,et al.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs , 2007, Science.

[162]  A. Eyre-Walker,et al.  The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans , 2006, Genetics.

[163]  F. Galibert,et al.  The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[164]  K. Lindblad-Toh,et al.  Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B , 2013, Genome Biology.

[165]  J. Trent,et al.  Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor , 2015, Genome research.

[166]  Å. Hedhammar,et al.  Mortality in insured Swedish dogs: rates and causes of death in various breeds , 1997, Veterinary Record.

[167]  P. McGreevy,et al.  Epidemiological associations between brachycephaly and upper respiratory tract disorders in dogs attending veterinary practices in England , 2015, Canine Genetics and Epidemiology.

[168]  B. Gandolfi,et al.  Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats. , 2016, Developmental biology.

[169]  E. Ostrander,et al.  Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-Based Diagnostic Test , 2015, Molecular Cancer Research.

[170]  A. M. Okeyo,et al.  Genetics of adaptation in domestic farm animals: a review , 2010 .