Abstract
In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects 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. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two 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 highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.
Highlights
Visna/Maedi virus (VMV) and its closely related North American counterpart, ovine progressive pneumonia virus (OPPV), are small ruminant lentiviruses (SRLV) of the retroviridae family that infect sheep around the world
In addition to its association with susceptibility to OPPV infection, transmembrane protein 154 gene (TMEM154) was recently reported to be associated with the abundance of integrated provirus in Rambouillet, Polypay, and Columbia sheep in the U.S [10]. These observations suggest that removing sheep with the most susceptible TMEM154 alleles may help eradicate OPPV and protect flocks from reinfection. While these findings show promise for improving U.S sheep populations, it is important to identify which other populations around the world may be impacted by highly-susceptible TMEM154 haplotypes
The availability of next-generation whole genome sequence data from the International Sheep Genomics Consortium (ISGC) provided the opportunity to directly determine TMEM154 genotypes in silico for 75 sheep sampled from 39 breeds and two wild species from around the world (45 groups in total)
Summary
Visna/Maedi virus (VMV) and its closely related North American counterpart, ovine progressive pneumonia virus (OPPV), are small ruminant lentiviruses (SRLV) of the retroviridae family that infect sheep around the world (for review see [1]). Disease progression is associated with severe clinical signs that include difficulty breathing, chronic wasting, loss of motor control, and arthritis. The impact of SRLV infection is considerable when the virus is introduced into a naıve flock with susceptible sheep. The mortality in such flocks may reach 30% per year after a few years [5]. Once established in a ewe flock, subclinical infection weakens the resistance to disease, decreases fertility, and reduces lamb production [6]. Complications of SRLV infections lead to animal pain, disability, early culling, and increased labor
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