Associate Adjunct Prof
Offices and Labs
Profile IntroductionMy research interests involve investigating the genetics of traits in the horse that are economically and medically important and/or are useful models for other species, including humans. Most recently I identified a long terminal repeat insertion in a calcium ion channel gene, TRPM1, as the causal variant for both a white spotting pattern in horses (leopard complex spotting) and an eye disorder (congenital stationary night blindness). Work is on-going to understand the role that TRPM1 plays in the disruption of pigmentation. I am also investigating the genetics of several other pigmentation phenotypes and/or ocular disorders, among these is the second most common tumor in the horse, limbal squamous cell carcinoma. The primary goal of my research program is to develop tools that will assist animal breeders in making informed mating decisions and work towards better management practices, by understanding the biological mechanisms behind complex heritable traits.
|2001||Ph.D.||Veterinary Science||University of Kentucky|
|1996||B.S.||Agriculture||University of Florida|
Leopard complex spotting in horses as a genetic model for human vitiligo
Leopard complex spotting is characterized by white depigmentation patterns observed in several breeds of horses. Akin to human generalized vitiligo , these spotting patterns in horse are bilateral and symmetrical and are characterized by the progressive loss of pigment as the horse ages. Ocular diseases have been associated with both vitiligo in humans and leopard complex spotting in horses. The inheritance of these depigmentation patterns in horse is also polygenic but one locus , namely LP, controls for the presence or absence of these spotting patterns while modifiers are thought to contribute to the amount of white spotting observed. A 1378bp insertion in the calcium ion channel gene, Transient Receptor Potential Cation Channel Subfamily M, Member 1 (TRPM1,) is believed to be the cuase of both LP and one of the associated ocular conditions (CSNB). However the precise functional mechanims that this insertion plays is not understood. Additionally one modifying locus has been investigated, PATN1, and a dominant allele results in large amounts of dipigmentaiton. However the precise molecular mechnaims of PATN1 is not yet understood. The goal of this project is to better define the functional role of the TRPM1 insertion in pigmentaiton while using genomic approaches to identify other genes that modify LP. Our hope is that studying this naturally occuring model of vitiligo will unravel the biochemical mechanisms explaining both melanocyte loss and ocular issues in vitiligo.
The genetics of ocular squamous cell carcinoma in horses
Squamous cell carcinoma (SCC) is the most common form of cancer of the equine eye and the second most common tumor of the horse overall. The most common ocular locations for SCC are the nictitating membrane and the limbus. Ocular SCC originating at the limbus (LSCC) can spread more deeply and laterally through the membrane and into the corneal region of the eye and can quickly lead to visual impairment and destruction of the eye. Furthermore, no treatment has a 100% efficacy and reoccurrence rates within a year are high. The etiopathogenesis of LSCC is not entirely understood but several factors including ultraviolet radiation, pigmentation surrounding the eye, nutrition, viral agents, hormonal, immunological, and genetics are thought to be involved. Of these, genetics is the least known and is the focus of study for this project. Interesting, Haflingers appear to be overrepresented for this cancer with two retrospective studies identifying 69% and 26% of the affected horses as Haflingers. Additionally, a statistically lower age of onset amongst the affected Haflingers (average age 8.7 years) compared to other breeds (12.1 years) was detected (T = 3.59, P = 0.002). Taken together, high prevalence in a single breed and lower mean age of onset, these data are indicative of a genetic basis for risk of disease in this breed. Currenlty genetic and genomic approaches are being utilized to identify and interogate associated loci.
CBS Grad Group Affiliations
Specialties / Focus
- Integrated Genetics and Genomics
- Animal Genomics
Graduate Groups not Housed in CBS
Lassaline, M., Cranford, T.L., Latimer, C.A., Bellone, R. (2014) Limbal squamous cell carcinoma in Haflinger horses. Veterinary Ophthalmology doi: 10.1111/vop.12229.http://onlinelibrary.wiley.com/doi/10.1111/vop.12229/full
Ludwig, A., Reissmann, M., Benecke, N., Bellone, R., Sandoval-Castellanos, E., Cieslak, M., Fortes, G.G., Morales-Muñiz, A., Hofreiter, M., & Pruvost, M. (2014) 25,000 years fluctuating selection on leopard complex spotting and congenital night blindness in horses. PHIL TRANS R SOC B DOI: 10.1098/rstb.2013.0386.
Fritz, K.L., Kaese, H.J., Valberg, S.J., Hendrickson, J.A., Rendahl, A.K., Bellone, R.R., Dynes, K.M.. Wagner, M.L., Lucio, M.A., Cuomo, F.M., Brinkmeyer-Langford, C.L., Skow, L.C., Mickelson, J.R., Rutherford, M.S., & McCue, M.E. (2013) Genetic risk factors for insidious Equine Recurrent Uveitis in Appaloosa horses. Animal Genetics 45(3):392-399.http://onlinelibrary.wiley.com/doi/10.1111/age.12129/full
Promerová, M., Andersson, L.S., Juras, R., Penedo, M.C.T., Reissmann, M., Tozaki, T., Bellone, R., Dunner, S., Hořín, P., Imsland, F., Imsland, P., Mikko, S., Modrý, D., Roed, K.H., Schwochow, D., Vega-Pla, J.L., Yeganeh, H.M., Mashouf, N.Y., Cothran, E.G., Lindgren, G., & Andersson, L. (2013) World-wide frequency distribution of the ‘Gait keeper’ mutation in the DMRT3 gene. Animal Genetics 45(2): 274–282.http://onlinelibrary.wiley.com/doi/10.1111/age.12120/full
Bellone, R.R., Holl, H., Setaluri, V., Devi, S., Maddodi, N., Archer, S., Sandmeyer, L., Ludwig, A., Foerster, D., Pruvost, M., Reissmann, M., Bortfeldt, R., Adelson, D.L., Lim, S.L., Nelson, J., Haase, B., Engensteiner, M., Leeb, T., Forsyth, G., Mienaltowski, M.J., Mahadevan, P., Hofreiter, M., Paijmans, J. L.A., Gonzalez-Fortes, G., Grahn, B., & Brooks, S.A. (2013) Evidence for a Retroviral Insertion in TRPM1 as the Cause of Congenital Stationary Night Blindness and Leopard Complex Spotting in the Horse. PLoS ONE 8(10):e78280 (doi:10.1371/journal.pone.0078280).http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0078280
Haase, B., Signer-Hasler, H., Binns, M.M., Obexer-Ruff, G., Hauswirth, R., Bellone, R., Burger, D., Rieder, S., Wade, C., & Leeb, T. (2013) Accumulating mutations in series of haplotypes at the KIT and MITF loci are major determinants of white markings in Franches-Montagnes horses. PLoS ONE 8(9):e75071 (doi:10.1371/journal.pone.007507).http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075071
Hauswirth, R., Jude, R., Haase, B., Bellone, R.R., Archer, S., Holl, H., Brooks, S.A., Tozaki, T., Penedo, M.C.T., Rieder, S., & Leeb, T. (2013) Novel variants in the KIT and PAX3 gene in horses with white spotted coat colour phenotypes. Animal Genetics. 44(6):763-765. http://onlinelibrary.wiley.com/doi/10.1111/age.12057/full
Makvandi-Nejad, S., Hoffman, G.E., Allen, J.J., Chu, E., Gu, E., Chandler, A.M., Loredo, A.I., Bellone, R.R., Mezey, J.G., Brooks, S.A., & Sutter, N.B. (2012) Four Loci Explain 83% of Size Variation in the Horse. PLoS One 7(7):e39929. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039929
Sandmeyer, L. S., Bellone, R.R., Archer, S., Bauer, B. S., Nelson, J., Forsyth, G. & Grahn, B. H. (2012) Congenital stationary night blindness is associated with the leopard complex in the miniature horse. Veterinary Ophthalmology. 15:18-22.http://onlinelibrary.wiley.com/doi/10.1111/j.1463-5224.2011.00903.x/full
Pruvost, M., Bellone, R., Beneck, N., Sandoval-Castellanos, E., Cieslak, M.,Kuznetsova, T., Morales-Muñiz, A., O’Connor, T., Reissmann, M., Hofreiter, M., & Ludwig, A. (2011) Genotypes of predomestic horses match phenotypespainted in Paleolithic works of cave art. PNAS 108(46):186260-18630.http://www.pnas.org/content/108/46/18626.long
Bellone R.R., S. Archer S., Wade, C.M., Cuka-Lawson, C., Haase, B., Leeb,T., Forsyth, G., Sandmeyer, L., & Grahn, B. (2010) Association analysis of candidate SNPs in TRPM1 with leopard complex spotting (LP) and congenital stationary night blindness (CSNB) in horses. Animal Genetics 41(Suppl. 2): 207.http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2052.2010.02119.x/full
Brooks, S.A., Makvandi-Nejad, S., Chu, E., Allen, J., Streeter, C., Gu, E., McCleery, B., Murphy, B.A., Bellone, R., & Sutter, N.B. (2010) Morphological Variation in the Horse: Defining Complex Traits of Body Size and Shape. Animal Genetics 41(Suppl. 2):159-165.http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2052.2010.02127.x/full
Bellone, R.R. (2010) Pleiotropic effects of pigmentation genes in horses. Animal Genetics 41(Suppl. 2):100–110. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2052.2010.02116.x/full
Bellone, R., Forsyth, G., Leeb, T., Archer, S., Sigurdsson, S., Mauceli, E., Engensteiner, M., Bailey, E., Sandmeyer, L., Grahn, B., Lindblad-Toh, K., & Wade, C. (2010) Fine-mapping and Mutation Analysis of TRPM1 a Candidate Gene for Leopard Complex (LP) Spotting and Congenital Stationary Night Blindness (CSNB) in Horses. Briefings in Functional Genomics 9(3):193-207.http://bfg.oxfordjournals.org/content/9/3/193.full.pdf+html
Wade, C.M., Giulotto, E., Sigurdsson, S., Zoli, M., Gnerre, S., Imsland, F., Lear, T.L., Adelson, D.L., Bailey, E., Bellone, R.R., Blöcker, H., Distl, O., Edgar, R.C., Garber, M., Leeb, T., Mauceli, E., MacLeod, J.N., Penedo, M.C.T., Raison, J.M., Sharpe, T., Vogel, J., Andersson, L., Antczak, D.F., Biagi, T., Binns, M.M., Chowdhary, B.P., Coleman, S.J., Della Valle, G., Fryc, S., Guérin, G., Hasegawa, T., Hill, E.W., Jurka, J., Kiialainen, A., Lindgren, G., Liu, J., Magnani, E., Mickelson, J.R., Murray, J., Nergadze, S.G., Onofrio, R., Pedroni, S., Piras, M.F., Raudsepp, T., Rocchi, M., Røed, K.H., Ryder, O.A., Searle S., Skow, L., Swinburne, J.E., Syvänen, A.C., Tozaki, T., Valberg, S.J., Vaudin, M., White, J.R., Zody, M.C., Broad Institute Genome Sequencing Platform, Broad Institute Whole Genome Assembly Team, Lander, E.S., & Lindblad-Toh , K. (2009) Genome sequence, comparative analysis and population genetics of the domestic horse (Equus caballus). Science 326(5954):865-867.http://www.sciencemag.org/content/326/5954/865.full
Cook, D., Brooks, S., Bellone, R., & Bailey, E. (2008) Missense Mutation in Exon 2 of SLC36A1 Responsible for Champagne Dilution in Horses. PLoS Genetics 4(9): e1000195 (doi:10.1371/journal.pgen.1000195).http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000195
Bellone, R., Brooks, S., Murphy, B., Sandmeyer, L., Forsyth, G., Archer, S., Bailey, E., & Grahn, B. (2008) Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in Appaloosa horses (Equus caballus). Genetics 179:1861-1870.http://www.genetics.org/content/179/4/1861.long