National Animal Genome Research Program - UNIVERSITY OF CALIFORNIA, DAVIS

Project Director
Bannasch, D.

Recipient Organization
UNIVERSITY OF CALIFORNIA, DAVIS
410 MRAK HALL
DAVIS,CA 95616-8671

Performing Department
POPULATION HEALTH & REPRODUCTION

Non Technical Summary
Neuroaxonal dystrophy (NAD) is a disease characterized by the acute onset of neurologic signs in foals at 4-6 months of age. Neuroaxonal dystrophy is considered the basic underlying disease of equine degenerative myeloencephalopathy (EDM), another neurologic condition in horses that presents with similar changes. Horses affected with this condition are unsuitable as performance animals and are often euthanized due to the severity of the condition. At this time, a definitive diagnosis of NAD and EDM can only be made upon examination of the spinal cord and brainstem once the horse has died. The discovery of an underlying genetic mutation that is causative for NAD would allow veterinarians to test for the disease in neurologically abnormal horses in order to diagnose the condition. In addition, a genetic test would aid horse breeders in making decisions designed to decrease the overall prevalence of this disease. In order to identify the cause of this disease we have used genetic tools to define a chromosomal location for the disease. We propose to use gene mapping techniques to narrow the window.

Animal Health Component

100%

Research Effort Categories

Basic

(N/A)

Applied

(N/A)

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
303	3810	1080	30%
304	3810	1080	30%
305	3810	1080	10%
311	3810	1080	30%

Knowledge Area
311 - Animal Diseases; 305 - Animal Physiological Processes; 303 - Genetic Improvement of Animals; 304 - Animal Genome;

Subject Of Investigation
3810 - Horses, ponies, and mules;

Field Of Science
1080 - Genetics;

Keywords

Goals / Objectives
Create shared genomic tools and reagents and sequence information to enhance the understanding and discovery of genetic mechanisms affecting traits of interest. Facilitate the development and sharing of animal populations and the collection and analysis of new, unique and interesting phenotypes. Develop, integrate and implement bioinformatics resources to support the discovery of genetic mechanisms that underlie traits of interest.

Project Methods
Neuroaxonal dystrophy (NAD) is a disease characterized by the acute onset of neurologic signs in foals at 4-6 months of age. Neuroaxonal dystrophy is considered the basic underlying disease of equine degenerative myeloencephalopathy (EDM), another neurologic condition in horses that presents with similar changes. Neuroaxonal dystrophy has been associated with neurologic disease in humans, sheep, cats, dogs and horses and, in all species, an underlying genetic cause for the disease has either been identified (humans) or suspected (sheep, cats, dogs). In horses, it appears likely that the disease is inherited and this has been supported by breeding studies in Morgan and Appaloosa horses. We have identified a group of related Quarter horses that are affected with NAD. As the entire horse genome is sequenced, we have the ability to map the location of a potential genetic mutation associated with NAD. The purpose of this study is to perform high resolution mapping of previously identified candidate regions. We further aim to sequence candidate genes identified by the fine structure mapping. We have performed a genome-wide association study with the Illumina Equine 60K single nucleotide polymorphism (SNP) array of NAD in Quarter horses utilizing 37 affected and 66 control horses and identified a sub-chromosomal region (3 Mb) of genome wide association (p genome= 2 x 10-4). There are two strong candidate genes within this region that are both expressed in the central nervous system. We hypothesize that a mutation in one of these genes (gene "A") is significantly associated with cases of NAD. In order to test our hypothesis, we intend to genotype the 37 affected and a total of 100 control horses for additional SNPs in this region to determine if there is a significant association between the alleles identified in affected versus control horses. Fine mapping SNPs will be selected from a worldwide database (dbSNP) across the candidate region at a distance of 35-40 per Mb (105-120 total). SNPs will be selected with a preference towards SNPs that have been found in multiple breeds of horses. Once selected, the SNPs will be assigned into multiplexes (maximum of 37 SNPs per multiplex) with commercially available Sequenom software. The Sequenom iPlex Gold reaction will be used for genotyping individuals for each of the selected SNPs. Once genotyped, data will be imported into Haploview software and an association analysis will be performed across all SNPs. If the association remains strong candidate genes in the area will be sequenced.

Progress 05/10/10 to 09/30/13

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? This project was not funded (per PI)

Publications

Progress 01/01/11 to 12/31/11

Outputs
OUTPUTS: Data from multiple equine GWAS projects has been analyzed. A talk was presented on the specific analysis of GWAS data for equine neuroaxonal dystrophy (NAD) at the equine genomics workshop in Minnesota in July 2011. A poster was presented at the Plant and Animal Genome conference equine workshop in San Diego, CA. Talks were given to veterinary students and residents on equine genomics. New equine SNP arrays were utilized and evaluated and additional samples were collected from affected and unaffected horses. PARTICIPANTS: Carrie Finno DVM Dip ACVIM did her thesis dissertation on the genetic analysis of NAD. She is going to be finishing in June 2012 and has post-doctoral funding for a fellowship at the University of Minnesota. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Although the current SNP arrays have been successfully used for genome wide association studies for simple traits more complex traits have not been mapped using this array. NAD appears to be a more complex trait although fine structure mapping is currently being used to test the theory that the lack of strong association is due to not enough SNPs for the length of LD within the breed rather than not enough samples.

Publications

McCue ME , Bannasch DL , Petersen JL , Gurr J , Bailey E , et al. 2012 A High Density SNP Array for the Domestic Horse and Extant Perissodactyla: Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies. PLoS Genet 8(1): e1002451.
Finno CJ, Higgins RJ, Aleman M, Ofri R, Hollingsworth SR, Bannasch DL, Reilly CM, Madigan JE. Equine degenerative myeloencephalopathy in Lusitano horses. J Vet Intern Med. 2011 Nov-Dec;25(6):1439-46.