[en] The 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.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Lequarré, Anne-Sophie ; Université de Liège - ULiège > Département clinique des animaux de compagnie et des équidés > Pathologie médicale des petits animaux
Abitbol M., Thibaud J.L., Olby N.J., Hitte C., Puech J.P., Maurer M., Pilot-Storck F., Hédan B., Dréano S., Brahimi S., Delattre D., André C., Gray F., Delisle F., Caillaud C., Bernex F., Panthier J.J., Aubin-Houzelstein G., Blot S., Tiret L. A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proceedings of the National Academy of Sciences USA 2010, 107:14775-14780.
Akey J.M., Ruhe A.L., Akey D.T., Wong A.K., Connelly C.F., Madeoy J., Nicholas T.J., Neff M.W. Tracking footprints of artificial selection in the dog genome. Proceedings of the National Academy of Sciences USA 2010, 107:1160-1165.
Asher L., Diesel G., Summers J.F., McGreevy P.D., Collins L.M. Inherited defects in pedigree dogs. Part 1: Disorders related to breed standards. The Veterinary Journal 2009, 182:402-411.
Aulchenko Y.S., Ripke S., Isaacs A., van Duijn C.M. GenABEL: An R library for genome-wide association analysis. Bioinformatics 2007, 23:1294-1296.
Bannasch D., Young A., Myers J., Truvé K., Dickinson P., Gregg J., Davis R., Bongcam-Rudloff E., Webster M.T., Lindblad-Toh K., Pedersen N. Localization of canine brachycephaly using an across breed mapping approach. PLoS ONE 2010, 5:e9632.
Boyko A.R., Quignon P., Li L., Schoenebeck J.J., Degenhardt J.D., Lohmueller K.E., Zhao K., Brisbin A., Parker H.G., vonHoldt B.M., Cargill M., Auton A., Reynolds A., Elkahloun A.G., Castelhano M., Mosher D.S., Sutter N.B., Johnson G.S., Novembre J., Hubisz M.J., Siepel A., Wayne R.K., Bustamante C.D., Ostrander E.A. A simple genetic architecture underlies morphological variation in dogs. PLoS Biology 2010, 8:e1000451.
Cadieu E., Neff M.W., Quignon P., Walsh K., Chase K., Parker H.G., Vonholdt B.M., Rhue A., Boyko A., Byers A., Wong A., Mosher D.S., Elkahloun A.G., Spady T.C., André C., Lark K.G., Cargill M., Bustamante C.D., Wayne R.K., Ostrander E.A. Coat variation in the domestic dog is governed by variants in three genes. Science 2009, 326:150-153.
Chase K., Jones P., Martin A., Ostrander E.A., Lark K.G. Genetic mapping of fixed phenotypes: Disease frequency as a breed characteristic. Journal of Heredity 2009, 100:S37-S41.
Derrien T., Thézé J., Vaysse A., André C., Ostrander E.A., Galibert F., Hitte C. Revisiting the missing protein-coding gene catalog of the domestic dog. BMC Genomics 2009, 10:62.
Higgins A., Nicholas F.W. The breeding of pedigree dogs - Time for strong leadership. The Veterinary Journal 2008, 178:157-158.
Jokinen T.S., Metsähonkala L., Bergamasco L., Viitmaa R., Syrjä P., Lohi H., Snellman M., Jeserevics J., Cizinauskas S. Benign familial juvenile epilepsy in Lagotto Romagnolo dogs. Journal of Veterinary Internal Medicine 2007, 21:464-471.
Jones P., Chase K., Martin A., Davern P., Ostrander E.A., Lark K.G. Single-nucleotide-polymorphism-based association mapping of dog stereotypes. Genetics 2008, 179:1033-1044.
Kang H.M., Zaitlen N.A., Wade C.M., Kirby A., Heckerman D., Daly M.J., Eskin E. Efficient control of population structure in model organism association mapping. Genetics 2008, 178:1709-1723.
Karlsson E.K., Lindblad-Toh K. Leader of the pack: Gene mapping in dogs and other model organisms. Nature Reviews Genetics 2008, 9:713-725.
Karlsson E.K., Baranowska I., Wade C.M., Salmon Hillbertz N.H., Zody M.C., Anderson N., Biagi T.M., Patterson N., Pielberg G.R., Kulbokas E.J., Comstock K.E., Keller E.T., Mesirov J.P., von Euler H., Kämpe O., Hedhammar A., Lander E.S., Andersson G., Andersson L., Lindblad-Toh K. Efficient mapping of Mendelian traits in dogs through genome-wide association. Nature Genetics 2007, 39:1321-1328.
Lindblad-Toh K., Wade C.M., Mikkelsen T.S., et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 2005, 438:803-819.
Madsen M.B., Olsen L.H., Häggström J., Höglund K., Ljungvall I., Falk T., Wess G., Stephenson H., Dukes-McEwan J., Chetboul V., Gouni V., Proschowsky H.F., Cirera S., Karlskov-Mortensen P., Fredholm M. Identification of two loci associated with development of myxomatous mitral valve disease in Cavalier King Charles Spaniels. Journal of Heredity 2011, 10.1093/jhered/esr041.
Mausberg T.B., Wess G., Simak J., Keller L., Drögemüller M., Drögemüller C., Webster M.T., Stephenson H., Dukes-McEwan J., Leeb T. A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman pinschers. PLoS ONE 2011, 6:e20042.
Merveille A.C., Davis E.E., Becker-Heck A., Legendre M., Amirav I., Bataille G., Belmont J., Beydon N., Billen F., Clément A., Clercx C., Coste A., Crosbie R., de Blic J., Deleuze S., Duquesnoy P., Escalier D., Escudier E., Fliegauf M., Horvath J., Hill K., Jorissen M., Just J., Kispert A., Lathrop M., Loges N.T., Marthin J.K., Momozawa Y., Montantin G., Nielsen K.G., Olbrich H., Papon J.F., Rayet I., Roger G., Schmidts M., Tenreiro H., Towbin J.A., Zelenika D., Zentgraf H., Georges M., Lequarré A.S., Katsanis N., Omran H., Amselem S. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genetics 2011, 43:72-78.
Meurs K.M., Fox P.R., Norgard M., Spier A.W., Lamb A. A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher. Journal of Veterinary Internal Medicine 2007, 21:1016-1020.
Mogensen M.S., Karlskov-Mortensen P., Proschowsky H.F., Lingaas F., Lappalainen A., Lohi H., Jensen V.F., Fredholm M. Genome-wide association study I Dachshund: Identification of a major locus affecting intervertebral disc calcification. Journal of Heredity 2011, 10.1093/jhered/esr021.
Johansso Moller M., Chaudhary R., Hellmén E., Höyheim B., Chowdhary B., Andersson L. Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor. Mammalian Genome 1996, 7:822-830.
Olsson M., Meadows J.R.S., Truvé K., Rosengren Pielberg G., Puppo F., Mauceli E., Quilez J., Tonomura N., Zanna G., Docampo M.J., Bassols A., Avery A.C., Karlsson E.K., Thomas A., Kastner D.L., Bongcam-Rudloff E., Webster M.T., Sanchez A., Hedhammar A., Remmers E.F., Andersson L., Ferrer L., Tintlem L., Lindblad-Tohm K. 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 Genetics 2011, 20-21. 10.1371/journal.pgen.1001332.
Parker H.G., Ostrander E.A. Canine genomics and genetics: Running with the pack. PLoS Genetics 2005, 1:e58.
Price A.L., Patterson N.J., Plenge R.M., Weinblatt M.E., Shadick N.A., Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 2006, 38:904-909.
Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira M.A., Bender D., Maller J., Sklar P., de Bakker P.I., Daly M.J., Sham P.C. PLINK: A tool set for whole genome association and population-based linkage analyses. American Journal of Human Genetics 2007, 81:559-575.
Rosengren Pielberg G., Golovko A., Sundström E., Curik I., Lennartsson J., Seltenhammer M.H., Druml T., Binns M., Fitzsimmons C., Lindgren G., Sandberg K., Baumung R., Vetterlein M., Strömberg S., Grabherr M., Wade C.M., Lindblad-Toh K., Pontén F., Heldin C.H., Sölkner J., Andersson L. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genetics 2008, 40:1004-1009.
Salmon Hillbertz N.H., Isaksson M., Karlsson E.K., Hellmén E., Pielberg G.R., Savolainen P., Wade C.M., von Euler H., Gustafson U., Hedhammar A., Nilsson M., Lindblad-Toh K., Andersson L., Andersson G. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nature Genetics 2007, 39:1318-1320.
Seppälä, E.H., Jokinen, T.S., Fukata, M., Fukata, Y., Webster, M.T., Karlsson, E.K., Kilpinen, S., Steffen, F., Dietschi, E., Leeb, T., Eklund, R., Xiaochu, Z., Rilstone, J., Lindblad-Toh, K., Minassian, B.A., Lohi, H., 2011. LGI2 truncation causes a remitting focal epilepsy in dogs. PloS Genetics. doi:10.1371/journal.pgen.1002194.
Sutter N.B., Eberle M.A., Parker H.G., Pullar B.J., Kirkness E.F., Kruglyak L., Ostrander E.A. Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Research 2004, 14:2388-2396.
Tsai K.L., Clark L.A., Murphy K.E. Understanding hereditary diseases using the dog and human as companion model systems. Mammalian Genome 2007, 18:444-451.
Wess G., Schulze A., Butz V., Simak J., Killich M. Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups. Journal of Veterinary Internal Medicine 2010, 24:533-538.
Wilbe M., Jokinen P., Truvé K., Seppälä E.H., Karlsson E.K., Biagi T., Hughes A., Bannasch D., Andersson G., Hansson-Hamlin H., Lohi H., Lindblad-Toh K. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nature Genetics 2010, 42:250-254.
Yang J., Lee S.H., Goddard M.E., Visscher P.M. GCTA: A tool for genome-wide complex trait analysis. American Journal of Human Genetics 2011, 88:76-82.
