Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity

Authors: Heaton, Michael - Mike; Smith, Timothy - Tim; Freking, Bradley - Brad; Workman, Aspen; Bennett, Gary; Carnahan, Jacky; KALBFLEISCH, THEODORE - University Of Louisville

Submitted to: F1000Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2017
Publication Date: 8/2/2017
Publication URL: https://handle.nal.usda.gov/10113/5801840
Citation: Heaton, M.P., Smith, T.P.L., Freking, B.A., Workman, A.M., Bennett, G.L., Carnahan, J.K., Kalbfleisch, T.S. 2017. Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity. F1000Research. 6:1303. https://doi.org/10.12688/f1000research.12216.1.
DOI: https://doi.org/10.12688/f1000research.12216.1

Interpretive Summary: Having access to U.S. sheep genome sequences significantly improves the chances of identifying genes that may influence the health, welfare, and productivity of these animals. This report describes an online resource containing whole genome sequences for a diverse set of 96 U.S. rams from nine breeds and a composite line. The resource may be used to identify and decode gene variants present in U.S. sheep. The utility of this approach was demonstrated with three major genes known to affect litter size in sheep populations around the world. Litter size is a fundamental component of productivity and profitability in sheep production. Genes affecting litter size are of interest as producers strive to fine tune their sheep production to match their available resources and optimize long-term sustainability. Eleven distinct variants were observed that could affect function, including one previously known to increase litter size in the highly-prolific Finnsheep breed. Four other gene variants were discovered that may also affect litter size in Dorset, Dorper, White Dorper, Katahdin, Romanov, and Finnsheep breeds. Although anyone may access the DNA sequence information without restriction, the resource was designed primarily for use by researchers in academia, companies, private industry, and government agencies. Producers benefit when researchers discover and validate new gene variants because DNA-based tests for these variants may be incorporated into existing genetic testing platforms and used to select for important traits and manage production. Future diagnostic tests will be more accurate and dependable because they will be able to account for genetic diversity inherent in U.S. sheep populations and represented in this genomic resource.

Technical Abstract: Background: Access to sheep genome sequences significantly improves the chances of identifying genes that may influence the health, welfare, and productivity of these animals. Methods: A public, searchable DNA sequence resource for U.S. sheep was created with whole genome sequence (WGS) of 96 rams. The animals shared minimal pedigree relationships and represent nine popular U.S. breeds and a composite line. The genomes are viewable online with the user-friendly Integrated Genome Viewer environment, and may be used to identify and decode gene variants present in U.S. sheep. Results: The genomes had a combined average read depth of 16, and an average WGS genotype scoring rate and accuracy exceeding 99%. The utility of this resource was illustrated by characterizing three genes with 14 known coding variants affecting litter size in global sheep populations: growth and differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), and bone morphogenetic protein receptor 1B (BMPR1B). In the 96 U.S. rams, nine missense variants encoding 11 protein variants were identified. However, only one was previously reported to affect litter size (GDF9 V371M, Finnsheep). Two missense variants in BMP15 were identified that had not previously been reported: R67Q in Dorset, and L252P in Dorper and White Dorper breeds. Also, two novel missense variants were identified in BMPR1B: M64I in Katahdin, and T345N in Romanov and Finnsheep breeds. Based on the strict conservation of amino acid residues across placental mammals, the four variants encoded by BMP15 and BMPR1B are predicted to interfere with their function. However, preliminary analyses of litter sizes in small samples did not reveal a correlation with variants in BMP15 and BMPR1B with daughters of these rams. Conclusions: Collectively, this report describes a new resource for discovering protein variants in silico and identifies alleles for further testing of their effects on litter size in U.S. breeds.