Abstract
Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.
Highlights
Visna/Maedi virus (VMV) and caprine arthritis encephalitis virus (CAEV) are small ruminant lentiviruses (SRLV) of the retroviridae family [1] that infect sheep and goats in major sheep producing countries worldwide
We designed a genome-wide association study to test whether sheep might have genetic variation that protects against lentivirus infection
The biological function of TMEM154 is unknown, our results indicate that it plays an important role in lentivirus infection in sheep
Summary
Visna/Maedi virus (VMV) and caprine arthritis encephalitis virus (CAEV) are small ruminant lentiviruses (SRLV) of the retroviridae family [1] that infect sheep and goats in major sheep producing countries worldwide. Sheep do not usually display signs of clinical disease in the first two years of infection. The first signs of disease are often loss of body condition and indurative mastitis (i.e., thin ewe syndrome and hard udder). Severe clinical signs may include difficulty breathing, chronic wasting, loss of motor control, and arthritis. The impact of subclinical OPPV infection is significant and includes detrimental effects on sheep production from breeding through weaning [6,7,8]. Considering that losses are cumulative during an animal’s lifetime, the negative effects on ewe production and the sheep industry are substantial
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