Mammalian Genome

, Volume 23, Issue 1–2, pp 144–163 | Cite as

Copy number variation in the domestic dog

  • Carlos E. AlvarezEmail author
  • Joshua M. AkeyEmail author


Differences in the content and organization of DNA, collectively referred to as structural variation, have emerged as a major source of genetic and phenotypic diversity within and between species. In addition, structural variation provides an important substrate for evolutionary innovations. Here, we review recent progress in characterizing patterns of canine structural variation within and between breeds, and in correlating copy number variants (CNVs) with phenotypes. Because of the extensive phenotypic diversity that exists within and between breeds and the tantalizing examples of canine CNVs that influence traits such as skin wrinkling in Shar-Pei, dorsal hair ridge in Rhodesian and Thai Ridgebacks, and short limbs in many breeds such as Dachshunds and Corgis, we argue that domesticated dogs are uniquely poised to contribute novel insights into CNV biology. As new technologies continue to be developed and refined, the field of canine genomics is on the precipice of a deeper understanding of how structural variation and CNVs contribute to canine genetic diversity, phenotypic variation, and disease susceptibility.


Hyaluronic Acid Comparative Genomic Hybridization Segmental Duplication Skin Wrinkle Hypocretin Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors acknowledge members of the Akey and Alvarez labs for critical feedback on the manuscript. The authors thank J. Rowell for critical reading of the manuscript and L. Rybaczyk, C. Bartlett, and L. Hou for technical assistance. This study was supported in part by a research Grant (1R01GM076036) from the National Institutes of Health to JMA, and by a research Grant (R210602710) from the National Institutes of Health and funding from The Research Institute at Nationwide Children’s Hospital to CEA.


  1. Akey JM, Ruhe AL, Akey DT, Wong AK, Connelly CF, Madeoy J, Nicholas TJ, Neff MW (2010) Tracking footprints of artificial selection in the dog genome. Proc Natl Acad Sci USA 107:1160–1165PubMedGoogle Scholar
  2. Alkan C, Coe BP, Eichler EE (2011) Genome structural variation discovery and genotyping. Nat Rev Genet 12:363–376PubMedGoogle Scholar
  3. Alvarez CE, Sutcliffe JG (2002) Hypocretin is an early member of the incretin gene family. Neurosci Lett 324:169–172PubMedGoogle Scholar
  4. Bailey JA, Eichler EE (2006) Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet 7:552–664PubMedGoogle Scholar
  5. Boyko AR (2011) The domestic dog: man’s best friend in the genomic era. Genome Biol 12:216PubMedGoogle Scholar
  6. Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, von Holdt BM et al (2010) A simple genetic architecture underlies morphological variation in dogs. PLoS Biol 8:e1000451PubMedGoogle Scholar
  7. Breen M (2009) Update on genomics in veterinary oncology. Top Companion Anim Med 24:113–121PubMedGoogle Scholar
  8. Bridges CB (1936) The Bar “gene” duplication. Science 83:210–211PubMedGoogle Scholar
  9. Brooks MB, Gu W, Ray K (1997) Complete deletion of factor IX gene and inhibition of factor IX activity in a labrador retriever with hemophilia B. J Am Vet Med Assoc 211:1418–1421PubMedGoogle Scholar
  10. Brooks MB, Gu W, Barnas JL, Ray J, Ray K (2003) A line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 14:788–795PubMedGoogle Scholar
  11. Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG, Vonholdt BM, Rhue A, Boyko A, Byers A et al (2009) Coat variation in the domestic dog is governed by variants in three genes. Science 326:150–153PubMedGoogle Scholar
  12. Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA, Nix MA, Kerns JA, Schmutz SM, Millhauser GL, Barsh GS (2007) A beta-defensin mutation causes black coat color in domestic dogs. Science 318:1418–1423PubMedGoogle Scholar
  13. Capt A, Spirito F, Guaguere E, Spadafora A, Ortonne JP, Meneguzzi G (2005) Inherited junctional epidermolysis bullosa in the German Pointer: establishment of a large animal model. J Invest Dermatol 124:530–535PubMedGoogle Scholar
  14. Chen WK, Swartz JD, Rush LJ, Alvarez CE (2009) Mapping DNA structural variation in dogs. Genome Res 19:500–509PubMedGoogle Scholar
  15. Clark LA, Wahl JM, Rees CA, Murphy KE (2006) Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci USA 103:1376–1381PubMedGoogle Scholar
  16. Conrad DF, Hurles ME (2007) The population genetics of structural variation. Nat Genet 39:S30–S36PubMedGoogle Scholar
  17. Credille KM, Minor JS, Barnhart KF, Lee E, Cox ML, Tucker KA, Diegel KL, Venta PJ, Hohl D, Huber M et al (2009) Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs. Br J Dermatol 161:265–272PubMedGoogle Scholar
  18. Darwin C (1859) The origin of species. John Murray, LondonGoogle Scholar
  19. Detweiler DK, Hubben K, Patterson DF (1960) Survey of cardiovascular disease in dogs–preliminary report on the first 1,000 dogs screened. Am J Vet Res 21:329–359PubMedGoogle Scholar
  20. Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat Rev Genet 7:85–97PubMedGoogle Scholar
  21. Forman OP, Boursnell ME, Dunmore BJ, Stendall N, van den Sluis B, Fretwell N, Jones C, Wijmenga C, Rothuizen J, van Oost BA et al (2005) Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers. Anim Genet 36:497–501PubMedGoogle Scholar
  22. Georges M (2007) Mapping, fine mapping, and molecular dissection of quantitative trait loci in domestic animals. Annu Rev Genomics Hum Genet 8:131–162PubMedGoogle Scholar
  23. Gill JL, Tsai KL, Krey C, Noorai RE, Vanbellinghen JF, Garosi LS, Shelton GD, Clark LA, Harvey RJ (2012) A canine BCAN microdeletion associated with episodic falling syndrome. Neurobiol Dis 45:130–136PubMedGoogle Scholar
  24. Goldstein O, Guyon R, Kukekova A, Kuznetsova TN, Pearce-Kelling SE, Johnson J, Aguirre GD, Acland GM (2010a) COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia. Mamm Genome 21:398–408PubMedGoogle Scholar
  25. Goldstein O, Kukekova AV, Aguirre GD, Acland GM (2010b) Exonic SINE insertion in STK38L causes canine early retinal degeneration (erd). Genomics 96:362–368PubMedGoogle Scholar
  26. Goldstein O, Mezey JG, Boyko AR, Gao C, Wang W, Bustamante CD, Anguish LJ, Jordan JA, Pearce-Kelling SE, Aguirre GD et al (2010c) An ADAM9 mutation in canine cone–rod dystrophy 3 establishes homology with human cone–rod dystrophy 9. Mol Vis 16:1549–1569PubMedGoogle Scholar
  27. Gu W, Brooks M, Catalfamo J, Ray J, Ray K (1999) Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemost 82:1270–1275PubMedGoogle Scholar
  28. Gu W, Zhang F, Lupski JR (2008) Mechanisms for human genomic rearrangements. Pathogenetics 1:4PubMedGoogle Scholar
  29. Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009a) Mechanisms of change in gene copy number. Nat Rev Genet 10:551–564PubMedGoogle Scholar
  30. Hastings PJ, Ira G, Lupski JR (2009b) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5:e1000327PubMedGoogle Scholar
  31. Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP, Snijders A, Albertson DG, Pinkel D, Marra MA et al (2004) A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 36:299–303PubMedGoogle Scholar
  32. Kaessmann H (2009) Genetics. More than just a copy. Science 325:958–959PubMedGoogle Scholar
  33. Karlsson EK, Lindblad-Toh K (2008) Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet 9:713–725PubMedGoogle Scholar
  34. Kazazian HH Jr, Moran JV (1998) The impact of L1 retrotransposons on the human genome. Nat Genet 19:19–24PubMedGoogle Scholar
  35. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T, Hansen N, Teague B, Alkan C, Antonacci F et al (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453:56–64PubMedGoogle Scholar
  36. Kidd JM, Graves T, Newman TL, Fulton R, Hayden HS, Malig M, Kallicki J, Kaul R, Wilson RK, Eichler EE (2010) A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143:837–847PubMedGoogle Scholar
  37. Kropatsch R, Petrasch-Parwez E, Seelow D, Schlichting A, Gerding WM, Akkad DA, Epplen JT, Dekomien G (2010) Generalized progressive retinal atrophy in the Irish Glen of Imaal terrier is associated with a deletion in the ADAM9 gene. Mol Cell Probes 24:357–363PubMedGoogle Scholar
  38. Kukekova AV, Trut LN, Chase K, Kharlamova AV, Johnson JL, Temnykh SV, Oskina IN, Gulevich RG, Vladimirova AV, Klebanov S et al (2011) Mapping loci for fox domestication: deconstruction/reconstruction of a behavioral phenotype. Behav Genet 41:593–606PubMedGoogle Scholar
  39. Lee JA, Carvalho CM, Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235–1247PubMedGoogle Scholar
  40. Leonard JA, Wayne RK, Wheeler J, Valadez R, Guillen S, Vila C (2002) Ancient DNA evidence for old world origin of new world dogs. Science 298:1613–1616PubMedGoogle Scholar
  41. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376PubMedGoogle Scholar
  42. Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ 3rd, Zody MC et al (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438:803–819PubMedGoogle Scholar
  43. Lozier JN, Dutra A, Pak E, Zhou N, Zheng Z, Nichols TC, Bellinger DA, Read M, Morgan RA (2002) The Chapel Hill hemophilia a dog colony exhibits a factor VIII gene inversion. Proc Natl Acad Sci USA 99:12991–12996PubMedGoogle Scholar
  44. Lupski JR (2010) Retrotransposition and structural variation in the human genome. Cell 141:1110–1112PubMedGoogle Scholar
  45. Lupski JR, Stankiewicz P (2005) Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet 1:e49PubMedGoogle Scholar
  46. McGraw RA, Carmichael KP (2006) Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171:370–372PubMedGoogle Scholar
  47. Mealey KL, Bentjen SA, Gay JM, Cantor GH (2001) Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727–733PubMedGoogle Scholar
  48. Mealey KL, Northrup NC, Bentjen SA (2003) Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med Assoc 223:1453–1455PubMedGoogle Scholar
  49. Mellersh CS, Boursnell ME, Pettitt L, Ryder EJ, Holmes NG, Grafham D, Forman OP, Sampson J, Barnett KC, Blanton S et al (2006) Canine RPGRIP1 mutation establishes cone–rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88:293–301PubMedGoogle Scholar
  50. Neff MW, Robertson KR, Wong AK, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC (2004) Breed distribution and history of canine mdr1–1Delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci USA 101:11725–11730PubMedGoogle Scholar
  51. Nicholas TJ, Cheng Z, Ventura M, Mealey K, Eichler EE, Akey JM (2009) The genomic architecture of segmental duplications and associated copy number variants in dogs. Genome Res 19:491–499PubMedGoogle Scholar
  52. Nicholas TJ, Baker C, Eichler EE, Akey JM (2011) A high-resolution integrated map of copy number polymorphisms within and between breeds of the modern domesticated dog. BMC Genomics 12:414PubMedGoogle Scholar
  53. Ohno S (1970) Evolution by gene duplication. Springer, New YorkGoogle Scholar
  54. Olsson M, Meadows JR, Truve K, Rosengren Pielberg G, Puppo F, Mauceli E, Quilez J, Tonomura N, Zanna G, Docampo MJ et al (2011) A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. PLoS Genet 7:e1001332PubMedGoogle Scholar
  55. Onogi A, Nurimoto M, Sato Y, Morita M (2008) A chromosomal duplication that includes the canine microsatellite INRA21 in Labrador retrievers. Anim Genet 39:241–248PubMedGoogle Scholar
  56. Parker HG, Kukekova AV, Akey DT, Goldstein O, Kirkness EF, Baysac KC, Mosher DS, Aguirre GD, Acland GM, Ostrander EA (2007) Breed relationships facilitate fine-mapping studies: a 7.8 kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. Genome Res 17:1562–1571PubMedGoogle Scholar
  57. Parker HG, VonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG et al (2009) An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325:995–998PubMedGoogle Scholar
  58. Parker HG, Shearin AL, Ostrander EA (2010) Man’s best friend becomes biology’s best in show: genome analyses in the domestic dog. Annu Rev Genet 44:309–336PubMedGoogle Scholar
  59. Pele M, Tiret L, Kessler JL, Blot S, Panthier JJ (2005) SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum Mol Genet 14:1417–1427PubMedGoogle Scholar
  60. Pollinger JP, Bustamante CD, Fledel-Alon A, Schmutz S, Gray MM, Wayne RK (2005) Selective sweep mapping of genes with large phenotypic effects. Genome Res 15:1809–1819PubMedGoogle Scholar
  61. Quilez J, Short AD, Martinez V, Kennedy LJ, Ollier W, Sanchez A, Altet L, Francino O (2011) A selective sweep of >8 Mb on chromosome 26 in the boxer genome. BMC Genomics 12:339PubMedGoogle Scholar
  62. Rowell JL, McCarthy DO, Alvarez CE (2011) Dog models of naturally occurring cancer. Trends Mol Med 17(7):380–388PubMedGoogle Scholar
  63. Salmon Hillbertz NH, Isaksson M, Karlsson EK, Hellmen E, Pielberg GR, Savolainen P, Wade CM, von Euler H, Gustafson U, Hedhammar A et al (2007) Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat Genet 39:1318–1320PubMedGoogle Scholar
  64. Savolainen P, Zhang YP, Luo J, Lundeberg J, Leitner T (2002) Genetic evidence for an East Asian origin of domestic dogs. Science 298:1610–1613PubMedGoogle Scholar
  65. Schatzberg SJ, Olby NJ, Breen M, Anderson LV, Langford CF, Dickens HF, Wilton SD, Zeiss CJ, Binns MM, Kornegay JN et al (1999) Molecular analysis of a spontaneous dystrophin ‘knockout’ dog. Neuromuscul Disord 9:289295Google Scholar
  66. Schuetz EG (2004) Lessons from the CYP3A4 promoter. Mol Pharmacol 65:279–281PubMedGoogle Scholar
  67. Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA (2002) Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet 11:1823–1833PubMedGoogle Scholar
  68. Slack A, Thornton PC, Magner DB, Rosenberg SM, Hastings PJ (2006) On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet 2:e48PubMedGoogle Scholar
  69. Smith FW Jr, Buoen LC, Weber AF, Johnston SD, Randolph JF, Waters DJ (1989) X-chromosomal monosomy (77, X0) in a Doberman Pinscher with gonadal dysgenesis. J Vet Intern Med 3:90–95PubMedGoogle Scholar
  70. Smith BF, Yue Y, Woods PR, Kornegay JN, Shin JH, Williams RR, Duan D (2011) An intronic LINE-1 element insertion in the dystrophin gene aborts dystrophin expression and results in Duchenne-like muscular dystrophy in the corgi breed. Lab Invest 91:216–231PubMedGoogle Scholar
  71. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18:74–82PubMedGoogle Scholar
  72. Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455PubMedGoogle Scholar
  73. Tsujino N, Sakurai T (2009) Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 61:162–176PubMedGoogle Scholar
  74. van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C (2002) Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet 11:165–173Google Scholar
  75. Verardi A, Lucchini V, Randi E (2006) Detecting introgressive hybridization between free-ranging domestic dogs and wild wolves (Canis lupus) by admixture linkage disequilibrium analysis. Mol Ecol 15:2845–2855PubMedGoogle Scholar
  76. Vonholdt BM, Pollinger JP, Lohmueller KE, Han E, Parker HG, Quignon P, Degenhardt JD, Boyko AR, Earl DA, Auton A et al (2010) Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature 464:898–902PubMedGoogle Scholar
  77. Wang W, Kirkness EF (2005) Short interspersed elements (SINEs) are a major source of canine genomic diversity. Genome Res 15:1798–1808PubMedGoogle Scholar
  78. Wiik AC, Wade C, Biagi T, Ropstad EO, Bjerkas E, Lindblad-Toh K, Lingaas F (2008) A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone–rod dystrophy in standard wire-haired dachshund. Genome Res 18:1415–1421PubMedGoogle Scholar
  79. Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, Hebert M, Jones KN, Shu Y, Kitzmiller K et al (2007) Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 80:1037–1054PubMedGoogle Scholar
  80. Zanna G, Fondevila D, Bardagí M, Docampo MJ, Bassols A, Ferrer L (2008) Cutaneous mucinosis in shar-pei dogs is due to hyaluronic acid deposition and is associated with high levels of hyaluronic acid in serum. Vet Dermatol 19:314–318PubMedGoogle Scholar
  81. Zeng R, Farias FH, Johnson GS, McKay SD, Schnabel RD, Decker JE, Taylor JF, Mann CS, Katz ML, Johnson GC et al (2011) A truncated retrotransposon disrupts the GRM1 coding sequence in Coton de Tulear dogs with Bandera’s neonatal ataxia. J Vet Intern Med 25:267–272PubMedGoogle Scholar
  82. Zhang F, Gu W, Hurles ME, Lupski JR (2009a) Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10:451–481PubMedGoogle Scholar
  83. Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR (2009b) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 41:849–853PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Center for Human and Molecular GeneticsThe Research Institute at Nationwide Children’s HospitalColumbusUSA
  2. 2.Department of PediatricsThe Ohio State University College of MedicineColumbusUSA
  3. 3.Department of Veterinary Clinical SciencesThe Ohio State University College of Veterinary MedicineColumbusUSA
  4. 4.Department of Genome SciencesUniversity of WashingtonSeattleUSA

Personalised recommendations