Skip to main content
ARS Home » Plains Area » Clay Center, Nebraska » U.S. Meat Animal Research Center » Genetics and Animal Breeding » Research » Publications at this Location » Publication #330322

Title: Using diverse U.S. beef cattle genomes to identify missense mutations in EPAS1, a gene associated with pulmonary hypertension

item Heaton, Michael - Mike
item Smith, Timothy - Tim
item Carnahan, Jacky
item BASNAYAKE, VERONICA - Geneseek Inc, A Neogen Company
item QIU, JIANSHENG - Geneseek Inc, A Neogen Company
item SIMPSON, BARRY - Geneseek Inc, A Neogen Company
item KALBFLEISCH, THEODORE - University Of Louisville

Submitted to: F1000Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2016
Publication Date: 9/16/2016
Citation: Heaton, M.P., Smith, T.P.L., Carnahan, J.K., Basnayake, V., Qiu, J., Simpson, B., Kalbfleisch, T.S. 2016. Using diverse U.S. beef cattle genomes to identify missense mutations in EPAS1, a gene associated with pulmonary hypertension. F1000Research. 5:2003. doi:10.12688/f1000research.9254.2.

Interpretive Summary: Having access to an animal’s whole genome sequence is analogous to having the complete set of instructions for its self-assembly and operation. The difference is, the instructions are written in a language that is not yet fully understood. Access to genome sequences significantly improves the chances of identifying genes that may influence the health, welfare, and productivity of U.S. beef cattle. This report describes a freely accessible internet resource containing whole genome sequences for a diverse set of 96 U.S. beef sires from 19 breeds. The resource can be used to identify and decode gene variants present in the vast majority of U.S. beef cattle. The power of this approach was demonstrated by identifying mutations in a gene previously associated with high-mountain disease in Angus cattle. Cattle with this illness (also known as brisket disease) develop high blood pressure in their pulmonary arteries and subsequent heart failure as a consequence of being moved to summer pastures at high altitudes. This disease has also been recognized as an increasing problem in North American beef cattle in feedyards, and in dairy cattle. The present report describes eight different versions of a major gene (EPAS1) that is associated with brisket disease, and a high-throughput test for typing this gene in cattle. The test was used in 46 breeds of U.S. beef and dairy cattle to estimate the frequency of a genetic risk factor for disease. This test also is suitable for determining whether other EPAS1 gene variants are detrimental to the health and well-being of cattle in various production environments. The EPAS1 test and the associated information are available to researchers, companies, veterinarians, and producers for use without restriction.

Technical Abstract: The availability of whole genome sequence (WGS) data has made it possible to discover protein variants in silico. However, existing bovine WGS databases do not show data in a form conducive to protein variant analysis, and tend to under represent the breadth of genetic diversity in U.S. beef cattle. Thus, our first aim was to use 96 beef sires, sharing minimal pedigree relationships, to create a searchable and publicly viewable set of mapped genomes relevant for 19 popular breeds of U.S. cattle. Our second aim was to identify protein variants encoded by the bovine endothelial PAS domain-containing protein 1 gene (EPAS1), a gene associated with high-altitude pulmonary hypertension in Angus cattle. The identity and quality of genomic sequences were verified by comparing WGS genotypes to those derived from other methods. The average read depth, genotype scoring rate, and genotype accuracy exceeded 14, 99%, and 99%, respectively. The 96 genomes were used to discover four amino acid variants encoded by EPAS1 (E270Q, P362L, A671G, and L701F) and confirm two variants previously associated with disease (A606T and G610S). The six EPAS1 missense mutations were verified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays, and their frequencies were estimated in a separate collection of 1154 U.S. cattle representing 46 breeds. A rooted phylogenetic tree of eight polypeptide sequences provided a framework for evaluating the likely order of mutations and potential impact of EPAS1 alleles on the adaptive response to chronic hypoxia in U.S. cattle. This public, whole genome resource facilitates in silico identification of protein variants in diverse types of U.S. beef cattle, and provides a means of translating WGS data into a practical biological and evolutionary context for generating and testing hypotheses.