Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Leader of the pack: gene mapping in dogs and other model organisms

Key Points

  • The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour by using over 400 distinct dog breeds created by artificial selection. Dogs and humans have roughly the same genes, share many aspects of their environment and suffer similar diseases, including cancer, diabetes and epilepsy.

  • The canine genome project provided a complete genome sequence, a SNP map and an understanding of the haplotype structure, and now genome-wide SNP genotyping arrays make it possible to carry out whole-genome trait mapping.

  • Trait-mapping strategies that are possible in dogs include genome-wide association mapping, quantitative trait loci mapping, across-breed mapping and selection mapping. Although traits that segregate within breeds are amenable to whole-genome association, fixed phenotypes might require cross-breed mapping strategies.

  • The dog-breed populations are ideally suited to a two-stage genome-wide association mapping strategy. First, genome-wide association in hundreds of cases and controls identifies one or more 1 Mb regions of association. Second, fine-mapping in multiple breeds with the same phenotype refines the association to 10–100 kb regions that contain the mutations.

  • Many of the mutations that have been linked to dog phenotypes so far are regulatory and involve diverse mutational mechanisms, including copy number polymorphisms, short interspersed nuclear element insertions and repeat length polymorphisms. This suggests that mutations in dogs are likely to be similar in nature to those that underlie human complex traits.

  • Many other model organisms have significant trait-mapping potential, and, as with the dog, the unique population history and biology of each should be considered when developing the necessary tools. This work is underway in numerous domestic animals, including the chicken, cattle, the cat and the horse, and is proposed for several fish, including sticklebacks and tilapia.

Abstract

The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. We share many diseases with our canine companions, including cancer, diabetes and epilepsy, making the dog an ideal model organism for comparative disease genetics. Using newly developed resources, whole-genome association in dog breeds is proving to be exceptionally powerful. Here, we review the different trait-mapping strategies, some key biological findings emerging from recent studies and the implications for human health. We also discuss the development of similar resources for other vertebrate organisms.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Haplotype structure of the dog.
Figure 2: Two-stage mapping strategy.

References

  1. 1

    Lander, E. S. & Schork, N. J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994). A good description of the requirements for complex trait mapping.

    CAS  Article  Google Scholar 

  2. 2

    Bucan, M. & Abel, T. The mouse: genetics meets behaviour. Nature Rev. Genet. 3, 114–123 (2002).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Cook, M. C., Vinuesa, C. G. & Goodnow, C. C. ENU-mutagenesis: insight into immune function and pathology. Curr. Opin. Immunol. 18, 627–633 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Copeland, N. G., Jenkins, N. A. & Court, D. L. Recombineering: a powerful new tool for mouse functional genomics. Nature Rev. Genet. 2, 769–779 (2001).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Paigen, K. A miracle enough: the power of mice. Nature Med. 1, 215–220 (1995). A discussion of the mouse as the model organism of choice.

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Ostrander, E. A. & Kruglyak, L. Unleashing the canine genome. Genome Res. 10, 1271–1274 (2000).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Wayne, R. K. Limb morphology of domestic and wild canids: the influence of development on morphologic change. J. Morphol. 187, 301–319 (1986).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Fogle, B., Morgan, T. & Fogle, B. The New Encyclopedia of the Dog (Dorling Kindersley, New York, 2000).

    Google Scholar 

  9. 9

    American Kennel Club. The Complete Dog Book (eds Crowley, J. & Adelman, B.) (Howell Book House, New York, 1998).

  10. 10

    Patterson, D. F. et al. Research on genetic diseases: reciprocal benefits to animals and man. J. Am. Vet. Med. Assoc. 193, 1131–1144 (1988).

    CAS  PubMed  Google Scholar 

  11. 11

    Sargan, D. R. IDID: inherited diseases in dogs: web-based information for canine inherited disease genetics. Mamm. Genome 15, 503–506 (2004).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Sargan, D. R., Aguirre-Hernandez, J., Galibert, F. & Ostrander, E. A. An extended microsatellite set for linkage mapping in the domestic dog. J. Hered. 98, 221–231 (2007).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Acland, G. M. et al. Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans. Proc. Natl Acad. Sci. USA 95, 3048–3053 (1998).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Sidjanin, D. J. et al. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum. Mol. Genet. 11, 1823–1833 (2002).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Yuzbasiyan-Gurkan, V. et al. Linkage of a microsatellite marker to the canine copper toxicosis locus in Bedlington terriers. Am. J. Vet. Res. 58, 23–27 (1997).

    CAS  PubMed  Google Scholar 

  16. 16

    van De Sluis, B., Rothuizen, J., Pearson, P. L., van Oost, B. A. & Wijmenga, C. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum. Mol. Genet. 11, 165–173 (2002).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Jonasdottir, T. J. et al. Genetic mapping of a naturally occurring hereditary renal cancer syndrome in dogs. Proc. Natl Acad. Sci. USA 97, 4132–4137 (2000).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Lingaas, F. et al. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum. Mol. Genet. 12, 3043–3053 (2003).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Mignot, E. et al. Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment. Proc. Natl Acad. Sci. USA 88, 3475–3478 (1991). This paper describes the identification of the first canine SINE mutation.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005). A paper that described the canine genome sequence and haplotype structure.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Karlsson, E. K. et al. Efficient mapping of Mendelian traits in dogs through genome-wide association. Nature Genet. 39, 1321–1328 (2007). This paper describes the proof-of-principle studies for GWA mapping in the dog.

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Salmon Hillbertz, N. H. et al. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nature Genet. 39, 1318–1320 (2007). This paper reports the second mutation to be identified from the proof-of-principle experiments for GWA in the dog.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Giger, U., Sargan, D. R. & McNiel, E. A. in The Dog and its Genome (eds Ostrander, E. A., Giger, U. & Lindblad-Toh, K.) 249–289 (Cold Spring Harbor Laboratory Press, New York, 2006).

    Google Scholar 

  25. 25

    Little, C. C. Coat color in pointer dogs. J. Hered. 5, 244–248 (1914).

    Article  Google Scholar 

  26. 26

    Wright, S. The hairless dog. J. Hered. 8, 519–520 (1917).

  27. 27

    Whitney, L. F. Heredity of the trail barking propensity in dogs. J. Hered. 20, 561–562 (1929).

    Article  Google Scholar 

  28. 28

    Hutt, F. B., Rickard, C. G. & Field, R. A. Sex-linked hemophilia in dogs. J. Hered. 39, 3–9 (1948).

    Article  Google Scholar 

  29. 29

    Evans, J. P., Brinkhous, K. M., Brayer, G. D., Reisner, H. M. & High, K. A. Canine hemophilia B resulting from a point mutation with unusual consequences. Proc. Natl Acad. Sci. USA 86, 10095–10099 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Mellersh, C. S. et al. A linkage map of the canine genome. Genomics 46, 326–336 (1997).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Breen, M. et al. Chromosome-specific single-locus FISH probes allow anchorage of an 1800-marker integrated radiation-hybrid/linkage map of the domestic dog genome to all chromosomes. Genome Res. 11, 1784–1795 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Guyon, R. et al. A 1-Mb resolution radiation hybrid map of the canine genome. Proc. Natl Acad. Sci. USA 100, 5296–5301 (2003).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Breen, M. et al. An integrated 4249 marker FISH/RH map of the canine genome. BMC Genomics 5, 65 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Kirkness, E. F. et al. The dog genome: survey sequencing and comparative analysis. Science 301, 1898–1903 (2003).

    Article  PubMed  Google Scholar 

  35. 35

    Hartl, D. L. & Clark, A. G. Principles of Population Genetics (Sinauer Associates, Sunderland, Massachusets, 1997).

    Google Scholar 

  36. 36

    Peltonen, L., Palotie, A. & Lange, K. Use of population isolates for mapping complex traits. Nature Rev. Genet. 1, 182–190 (2000). An excellent review of the power of isolated populations for mapping genes that underlie complex traits.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Sutter, N. B. et al. Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Res. 14, 2388–2396 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Przeworski, M. The signature of positive selection at randomly chosen loci. Genetics 160, 1179–1189 (2002).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Wade, C. M., Karlsson, E. K., Mikkelsen, T. S., Zody, M. C. & Lindblad-Toh, K. in The Dog and its Genome (eds Ostrander, E. A., Giger, U. & Lindblad-Toh, K.) 179–208 (Cold Spring Harbor Laboratory Press, New York, 2006).

    Google Scholar 

  40. 40

    Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Florez, J. C., Hirschhorn, J. & Altshuler, D. The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu. Rev. Genomics Hum. Genet. 4, 257–291 (2003).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Lark, K. G., Chase, K. & Sutter, N. B. Genetic architecture of the dog: sexual size dimorphism and functional morphology. Trends Genet. 22, 537–544 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Sutter, N. B. et al. A single IGF1 allele is a major determinant of small size in dogs. Science 316, 112–115 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Jones, P. et al. Single-nucleotide-polymorphism-based association mapping of dog stereotypes. Genetics 179, 1033–1044 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Altshuler, D. & Daly, M. Guilt beyond a reasonable doubt. Nature Genet. 39, 813–815 (2007). A good recent review of human whole-genome association results

    CAS  Article  Google Scholar 

  47. 47

    Minnick, M. F., Stillwell, L. C., Heineman, J. M. & Stiegler, G. L. A highly repetitive DNA sequence possibly unique to canids. Gene 110, 235–238 (1992).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Bentolila, S. et al. Analysis of major repetitive DNA sequences in the dog (Canis familiaris) genome. Mamm. Genome 10, 699–705 (1999).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Vassetzky, N. S. & Kramerov, D. A. CAN a pan-carnivore SINE family. Mamm. Genome 13, 50–57 (2002).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Pele, M., Tiret, L., Kessler, J. L., Blot, S. & Panthier, J. J. 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, 1417–1427 (2005).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Clark, L. A., Wahl, J. M., Rees, C. A. & Murphy, K. E. Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc. Natl Acad. Sci. USA. 103, 1376–1381 (2006).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Lohi, H. et al. Expanded repeat in canine epilepsy. Science 307, 81 (2005). This article describes the identification of the first canine repeat length polymorphism.

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Kazemi-Esfarjani, P., Trifiro, M. A. & Pinsky, L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum. Mol. Genet. 4, 523–527 (1995).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Steingrimsson, E., Copeland, N. G. & Jenkins, N. A. Melanocytes and the microphthalmia transcription factor network. Annu. Rev. Genet. 38, 365–411 (2004).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Feldman, B., Poueymirou, W., Papaioannou, V. E., DeChiara, T. M. & Goldfarb, M. Requirement of FGF-4 for postimplantation mouse development. Science 267, 246–249 (1995).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Powles, N. et al. Regulatory analysis of the mouse Fgf3 gene: control of embryonic expression patterns and dependence upon sonic hedgehog (Shh) signalling. Dev. Dyn. 230, 44–56 (2004).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Wright, T. J. et al. Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction. Dev. Biol. 269, 264–275 (2004).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Giuffra, E. et al. A large duplication associated with dominant white color in pigs originated by homologous recombination between LINE elements flanking KIT. Mamm. Genome 13, 569–577 (2002).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Parker, H. G. et al. Breed relationships facilitate fine-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. Genome Res. 17, 1562–1571 (2007). A description of haplotype sharing in different breeds affected by Collie eye anomaly.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Van Laere, A. S. et al. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425, 832–836 (2003).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Eriksson, J. et al. Identification of the yellow skin gene reveals a hybrid origin of the domestic chicken. PLoS Genet. 4, e1000010 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Rosengren Pielberg, G. et al. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genet. 40, 1004–1009 (2008).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Schuster, S. C. Next-generation sequencing transforms today's biology. Nature Methods 5, 16–18 (2008).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Margulies, E. H. et al. An initial strategy for the systematic identification of functional elements in the human genome by low-redundancy comparative sequencing. Proc. Natl Acad. Sci. USA 102, 4795–4800 (2005).

    CAS  Article  Google Scholar 

  65. 65

    Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    The Broad Institute. Mammalian Genome Project. [online], (2008).

  67. 67

    Diamond, J. M. Guns, Germs, and Steel: the Fates of Human Societies (W. W. Norton & Co., New York, 1997).

    Google Scholar 

  68. 68

    Willham, R. L. From husbandry to science: a highly significant facet of our livestock heritage. J. Anim. Sci. 62, 1742–1758 (1986).

    Article  Google Scholar 

  69. 69

    Colosimo, P. F. et al. Widespread parallel evolution in sticklebacks by repeated fixation of Ectodysplasin alleles. Science 307, 1928–1933 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Sutter, N. & Ostrander, E. Dog star rising: The canine genetic system. Nature Rev. Genet. 5, 900–910 (2004).

    CAS  Article  Google Scholar 

  71. 71

    Gershwin, L. J. Veterinary autoimmunity: autoimmune diseases in domestic animals. Ann. N. Y Acad. Sci. 1109, 109–116 (2007).

    Article  PubMed  Google Scholar 

  72. 72

    Khanna, C. et al. The dog as a cancer model. Nature Biotechnol. 24, 1065–1066 (2006).

    CAS  Article  Google Scholar 

  73. 73

    Loscher, W., Schwartz-Porsche, D., Frey, H. H. & Schmidt, D. Evaluation of epileptic dogs as an animal model of human epilepsy. Arzneimittelforschung 35, 82–87 (1985).

    CAS  PubMed  Google Scholar 

  74. 74

    Overall, K. L. Natural animal models of human psychiatric conditions: assessment of mechanism and validity. Prog. Neuropsychopharmacol. Biol. Psychiatry 24, 727–776 (2000).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Vail, D. M. & MacEwen, E. G., Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest. 18, 781–792 (2000).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Mueller, F., Fuchs, B. & Kaser-Hotz, B. Comparative biology of human and canine osteosarcoma. Anticancer Res. 27, 155–164 (2007).

    CAS  PubMed  Google Scholar 

  77. 77

    Altshuler, D. et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

    Article  CAS  Google Scholar 

  78. 78

    Glickman, L., Glickman, N. & Thorpe, R. The Golden Retriever Club of America National Health Survey 1998–1999 [online], (1999).

  79. 79

    Hansen, K. & Khanna, C. Spontaneous and genetically engineered animal models; use in preclinical cancer drug development. Eur. J. Cancer 40, 858–880 (2004).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Khanna, C. et al. A randomized controlled trial of octreotide pamoate long-acting release and carboplatin versus carboplatin alone in dogs with naturally occurring osteosarcoma: evaluation of insulin-like growth factor suppression and chemotherapy. Clin. Cancer Res. 8, 2406–2412 (2002).

    CAS  PubMed  Google Scholar 

  81. 81

    Acland, G. M. et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol. Ther. 12, 1072–1082 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Acland, G. M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nature Genet. 28, 92–95 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Bennicelli, J. et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol. Ther. 16, 458–465 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Hillbertz, N. H. & Andersson, G. Autosomal dominant mutation causing the dorsal ridge predisposes for dermoid sinus in Rhodesian ridgeback dogs. J. Small Anim. Pract. 47, 184–188 (2006).

    Article  PubMed  Google Scholar 

  85. 85

    Copp, A. J., Greene, N. D. & Murdoch, J. N. The genetic basis of mammalian neurulation. Nature Rev. Genet. 4, 784–793 (2003).

    Article  PubMed  Google Scholar 

  86. 86

    Ackerman, L. L. & Menezes, A. H. Spinal congenital dermal sinuses: a 30-year experience. Pediatrics 112, 641–647 (2003).

    Article  PubMed  Google Scholar 

  87. 87

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Isaksson, M. et al. MLGA a rapid and cost-efficient assay for gene copy-number analysis. Nucleic Acids Res. 35, e115 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Wang, Y., Badea, T. & Nathans, J. Order from disorder: self-organization in mammalian hair patterning. Proc. Natl Acad. Sci. 103, 19800 (2006).

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Ornitz, D. M. & Itoh, N. Fibroblast growth factors. Genome Biol. 2, REVIEWS3005 (2001).

  91. 91

    Dourmishev, A. L., Dourmishev, L. A., Schwartz, R. A. & Janniger, C. K. Waardenburg syndrome. Int. J. Dermatol. 38, 656–663 (1999).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Tietz, W. A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance. Am. J. Hum. Genet. 15, 259–264 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Little, C. C. The Inheritance of Coat Color in Dogs (Comstock Pub. Associates, Ithaca, New York, 1957).

    Google Scholar 

  94. 94

    Metallinos, D. & Rine, J. Exclusion of EDNRB and KIT as the basis for white spotting in Border Collies. Genome Biol. 1, RESEARCH0004 (2000).

  95. 95

    van Hagen, M. A. et al. Analysis of the inheritance of white spotting and the evaluation of KIT and EDNRB as spotting loci in Dutch boxer dogs. J. Hered. 95, 526–531 (2004).

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Smith, S. D., Kelley, P. M., Kenyon, J. B. & Hoover, D. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. J. Med. Genet. 37, 446–448 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Tassabehji, M., Newton, V. E. & Read, A. P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8, 251–255 (1994).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Goldstein, O. et al. Linkage disequilibrium mapping in domestic dog breeds narrows the progressive rod-cone degeneration interval and identifies ancestral disease-transmitting chromosome. Genomics 18, 18 (2006).

    Google Scholar 

  99. 99

    Bradbury, J. Canine epilepsy gene mutation identified. Lancet Neurol. 4, 143 (2005).

    Article  PubMed  Google Scholar 

  100. 100

    Nadon, N. L., Duncan, I. D. & Hudson, L. D. A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development. Development 110, 529–537 (1990).

    CAS  PubMed  Google Scholar 

  101. 101

    Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Katz, M. L. et al. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem. Biophys. Res. Commun. 327, 541–547 (2005).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    Suber, M. L. et al. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc. Natl Acad. Sci. USA 90, 3968–3972 (1993).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Petersen-Jones, S. M., Entz, D. D. & Sargan, D. R. cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest. Ophthalmol. Vis. Sci. 40, 1637–1644 (1999).

    CAS  PubMed  Google Scholar 

  105. 105

    Kijas, J. W. et al. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc. Natl Acad. Sci. USA 99, 6328–6333 (2002).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Veske, A., Nilsson, S. E., Narfstrom, K. & Gal, A. Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57, 57–61 (1999).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Fyfe, J. C. et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103, 1573–1579 (2004).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Baldeschi, C. et al. Genetic correction of canine dystrophic epidermolysis bullosa mediated by retroviral vectors. Hum. Mol. Genet. 12, 1897–1905 (2003).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Capt, A. et al. Inherited junctional epidermolysis bullosa in the German Pointer: establishment of a large animal model. J. Invest. Dermatol. 124, 530–535 (2005).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Kramer, J. W. et al. A von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of German shorthaired pointer dogs. Vet. Pathol. 41, 221–228 (2004).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Venta, P. J., Li, J., Yuzbasiyan-Gurkan, V., Brewer, G. J. & Schall, W. D. Mutation causing von Willebrand's disease in Scottish Terriers. J. Vet. Intern. Med. 14, 10–19 (2000).

    CAS  PubMed  Google Scholar 

  112. 112

    Pele, M., Tiret, L., Kessler, J. L., Blot, S. & Panthier, J. J. 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, 1417–1427 (2005).

    CAS  Article  PubMed  Google Scholar 

  113. 113

    Sharp, N. J. et al. An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics 13, 115–121 (1992).

    CAS  Article  PubMed  Google Scholar 

  114. 114

    Mealey, K. L., Bentjen, S. A., Gay, J. M. & Cantor, G. H. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11, 727–733 (2001).

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Kijas, J. M. et al. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 61, 101–107 (1999).

    CAS  Article  PubMed  Google Scholar 

  116. 116

    Henthorn, P. S. et al. IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23, 69–74 (1994).

    CAS  Article  PubMed  Google Scholar 

  117. 117

    Benson, K. F. et al. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature Genet. 35, 90–96 (2003).

    CAS  Article  PubMed  Google Scholar 

  118. 118

    Zheng, K., Thorner, P. S., Marrano, P., Baumal, R. & McInnes, R. R. Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV. Proc. Natl Acad. Sci. USA 91, 3989–3993 (1994).

    CAS  Article  PubMed  Google Scholar 

  119. 119

    Everts, R. E., Rothuizen, J. & van Oost, B. A. Identification of a premature stop codon in the melanocyte-stimulating hormone receptor gene (MC1R) in Labrador and Golden retrievers with yellow coat colour. Anim. Genet. 31, 194–199 (2000).

    CAS  Article  PubMed  Google Scholar 

  120. 120

    Newton, J. M. et al. Melanocortin 1 receptor variation in the domestic dog. Mamm. Genome 11, 24–30 (2000).

    CAS  Article  PubMed  Google Scholar 

  121. 121

    Clark, L. A., Wahl, J. M., Rees, C. A. & Murphy, K. E. Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc. Natl Acad. Sci. USA 103, 1376–1381 (2006).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Mosher, D. S. et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 3, e79 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Candille, S. I. et al. A β-defensin mutation causes black coat color in domestic dogs. Science 318, 1418–1423 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank L. Andersson for helpful comments on the manuscript and our colleagues in the canine genetics community.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kerstin Lindblad-Toh.

Related links

Related links

FURTHER INFORMATION

Kerstin Lindblad-Toh's homepage

Glossary

Population bottleneck

A marked reduction in population size followed by the survival and expansion of a small random sample of the original population.

Linkage disequilibrium

(LD). Non-random association of alleles at two or more loci.

Haplotype block

A haplotype is the combination of alleles observed for one or more consecutive markers on a chromosome. A haplotype block is the region of a chromosome that contains no recombination.

Genome-wide association

(GWA). An approach that tests the whole genome for a statistical association between a marker and a trait in unrelated cases and controls.

Simple sequence length polymorphism

Short tandem repeats of DNA that vary in length.

Linkage mapping

A mapping method which uses pedigrees to find broad genomic regions (10–20 centimorgans) that adhere to an inheritance model proposed for the trait of interest.

1:1 orthologues

Pairs of single genes in two different species that are descended from the same ancestral gene.

Selection mapping

A mapping design that finds trait loci by searching for selective sweeps. A selective sweep describes the reduction or elimination of genetic variation in a region owing to strong selection.

Genome coverage

The number of times, on average, that each base is sequenced.

Genome assembly

The consensus sequence of many short reads put together (a read is a fragment of sequenced DNA).

N50 contig size

A contig is a segment of the genome assembly that contains no gaps. An N50 contig size means that half of all bases reside in contigs of this size or longer.

Supercontig

Consecutive contigs that are separated by gaps of known size and connected by paired end-reads.

Validation rate

The rate at which genotypes are confirmed using a different technology.

Coalescence modelling

Retrospective modelling of population history, used to generate expectations on genomic variation.

Penetrance

The proportion of individuals carrying a genetic variant who express the trait connected with that variant.

Phenocopy

Describes an individual without the trait mutation who nonetheless exhibit the trait owing to environmental or other causes.

Multiplicative risk

An inheritance model whereby disease risk increases by λ in heterozygotes and λ2 in homozygotes.

Corrects for multiple tests

The adjusting of p-values for statistical tests that include many markers, when the probability that significant values will occur by random chance is increased.

Assay conversion rate

The fraction of assays that work on a certain genotyping platform.

Call rate

The fraction of individuals that give genotyping calls for a particular SNP.

Copy number variant

(CNV). A genomic region that is longer than 1 kb and occurs a variable number of times.

Semi-dominant

A Mendelian inheritance pattern in which heterozygous individuals exhibit a phenotype that is intermediate to the two homozygous phenotypes.

Population stratification

The presence of multiple population subgroups that show limited interbreeding. When such subgroups differ both in allele frequency and in disease prevalence, this can lead to erroneous results in association studies.

Quantitative trait locus

(QTL). A stretch of DNA that is closely linked to a continuously variable phenotype.

Inbreeding coefficient

The probability that two alleles are identical by descent.

Short interspersed nuclear element

(SINE). Retrotransposons 200 bases long that are derived from a tRNA–Lysine and occur frequently throughout the canine genome.

Adaptive radiation

The evolution, through adaptation to different ecological niches, of phenotypic differences between individuals derived from a single species.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Karlsson, E., Lindblad-Toh, K. Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet 9, 713–725 (2008). https://doi.org/10.1038/nrg2382

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing