Impact of four ovine TMEM154 haplotypes on ewes during multiyear lentivirus exposure

Authors: Freking, Bradley - Brad; Murphy, Thomas - Tom; Chitko-Mckown, Carol; Workman, Aspen; Heaton, Michael - Mike

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/25/2022
Publication Date: 11/29/2022
Citation: Freking, B.A., Murphy, T.W., Chitko-McKown, C.G., Workman, A.M., Heaton, M.P. 2022. Impact of four ovine TMEM154 haplotypes on ewes during multiyear lentivirus exposure. International Journal of Molecular Sciences. 23(23). Article 14966. https://doi.org/10.3390/ijms232314966.
DOI: https://doi.org/10.3390/ijms232314966

Interpretive Summary: Ovine progressive pneumonia (OPP) is an incurable disease and results in millions of dollars of annual economic losses to the sheep industry. Genetic approaches to reducing susceptibility to this disease can be cost effective and a gene called TMEM154 has been identified as conferring different levels of susceptibility depending on the form of the protein produced by this gene. Data was evaluated from three overlapping prospective studies specifically designed to estimate the effects of each of the four most common TMEM154 protein variants defined by a genetic haplotype, on infection status and ewe lifetime productivity. In a common environment and with similar levels of natural virus exposure, less than 10% of the most favorable genotype ewes became infected through 5.5 yr. of age whereas > 80% of the most unfavorable genotype ewes were infected by 3.3 yr. of age. For ewes with one or two copies of the highly susceptible haplotypes “2” and ”3”, the infection prevalence steadily increased to nearly 100% by 55 months. The results showed both haplotypes “2” and “3” were completely dominant to haplotype “1” and are risk of infection alleles to be selected against. In addition, we found that the least susceptible combinations “1,1”, “1,4” and “4,4” provided similar levels of reduced susceptibility and similar reproductive performance. Lack of OPP disease progression was observed within animals containing two "4" alleles even after substantial time had occurred following serological conversion. The animals with the least susceptible combinations are seemingly not progressing to disease at the same rate as animals with highly susceptible combinations. Over five production years, ewes with the most favorable genotype weaned, on average, 2.1 more lambs and 40 kg greater weight of lamb than ewes with the unfavorable genotype. Combined analyses of all three experiments indicated that reduced susceptibility to OPP infection and increased levels of lifetime productivity would be expected from ewes that have two copies of the favorable versions of the TMEM154 gene and the most susceptible versions cause an equivalent risk of infection with just one copy present. Using average economic conditions during this experiment, these results equate to $171 in additional lifetime revenue for each ewe in the flock that is the most favorable genotype combination. Producers interested in using TMEM154 selection to reduce their flock’s genetic predisposition to OPP are encouraged to increase the frequency of TMEM154 haplotype “1” since it encodes a full-length protein with minimal difference to the ancestral version.

Technical Abstract: Polypeptide variation encoded by the ovine transmembrane protein 154 gene (TMEM154) is as-sociated with susceptibility to ovine lentivirus, the causative agent of Ovine Progressive Pneumonia (OPP) and Visna/Maedi. Our aim was to compare the four most prevalent TMEM154 haplotypes on the incidence of infection and ewe productivity during natural multiyear virus exposure. Prospective cohort studies were designed to test gene action and estimate effects of TMEM154 haplotypes encoding distinctive variant residues: K35 (“1”), I70 (“2”), ancestral (“3”), and A4del/M44 (“4”). Exposure consisted of co-mingling infected ewes at a rate greater than 30% with serological status evaluated every four months. For ewes with one or two copies of the highly susceptible haplotypes “2” and ”3”, the infection prevalence steadily increased to nearly 100% at 55 months. Haplotypes “2” and “3” were equally susceptible and dominant to haplotype “1”. A difference was not detected in the magnitude of effect with haplotype combinations of “1” and ”4”. The ewe infection prevalence with “1,1”; “1,4”; and “4,4” was 10% to 40% at 55 months. The latter suggested that two copies of the K35 amino acid substitution (“1”) were as effective as a homozygous TMEM154 “knockout” with the frame-shift deletion mutation (“4”) in reducing infection susceptibility. When considering ewe reproductive performance, a difference was not detected when comparing haplotypes “2”, and “3” to each other, or “1” and “4” to each other. This also indicated that ewes with two copies of the severely truncated versions of TMEM154 (“4,4”) had normal lamb productivity. Producers interested in using TMEM154 selection to reduce their flock’s genetic predisposition to OPP are encouraged to increase the frequency of TMEM154 haplotype K35 (“1”) since it encodes a full-length protein with minimal difference to the ancestral polypeptide.