|Heaton, Michael - Mike|
|Clawson, Michael - Mike|
|Chitko Mckown, Carol|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2012
Publication Date: 2/11/2013
Citation: Heaton, M.P., Kalbfleisch, T.S., Petrik, D.T., Simpson, B., Kijas, J.W., Clawson, M.L., Chitko MckKown, C.G., Harhay, G.P., Leymaster, K.A. 2013. Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep. PLoS One. 8(2):e55490. doi:10.1371/journal.pone.0055490. Interpretive Summary: Visna/Maedi and its closely related North American counterpart, ovine progressive pneumonia, are debilitating viral diseases that affect sheep in many parts of the world. The infection is life long and can cause respiratory distress, chronic wasting, loss of motor control, arthritis, and a mastitis condition called ‘hard udder’. Previous research has shown that sheep with a common variant form of the transmembrane protein 154 gene (TMEM154) were significantly less likely to become infected compared to those with highly susceptible forms of the same gene. The present survey of sheep from around the world showed that most breeds have highly-susceptible forms of TMEM154 and are predicted to have an increased genetic risk for infection. A genetic test for resolving the many forms of TMEM154 was developed to help predict an animal’s susceptibility to infection. Information necessary for developing similar genetic tests is provided for use without restriction. When combined with removing infected animals, selectively breeding sheep that are less susceptible to infection is expected to help eradicate disease and prevent flocks from reinfection.
Technical Abstract: In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affect millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. A missense mutation in TMEM154 encoding lysine (K) at position 35 was associated with reduced infection compared to ancestral haplotype alleles encoding glutamate (E) at position 35. Our aim was three-fold: 1) to estimate the frequency of the major TMEM154 susceptibility alleles in sheep populations around the world, 2) identify previously unreported alleles in these populations, and 3) develop an accurate genetic test for genotyping TMEM154. The average frequency of TMEM154 E35 among 74 breeds was 0.50 and indicated that susceptible alleles were prevalent in most breeds around the world. Analysis of TMEM154 in whole genome sequence data from an international panel of 75 sheep revealed 1,387 previously unreported polymorphisms in a 62 kb region and confirmed that the most susceptible haplotypes were distributed worldwide. Four of the 1,387 polymorphisms were novel missense mutations in the signal peptide (A13V) and extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization--time-of flight mass spectrometry (MALDI-TOF MS) assay was designed to these and eight previously reported missense and deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.