Abstract
BackgroundLike human immunodeficiency virus (HIV), ovine lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection.Methodology/Principal FindingsThis genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P = 9.2×10−7; empirical P = 0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1×10−5). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P = 0.006), and SYTL3 (P = 0.051). Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P = 0.001), C19orf42/TMEM38A (P = 0.047), and DLGAP1 (P = 0.092).Conclusions/SignificanceThese associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped virus assembly of human cytomegalovirus. Zinc finger transcription factors have been associated with positive selection for repression of retroviral replication. DLGAP1 binds and may regulate DLG1, a known regulator of HIV infectivity.
Highlights
Ovine lentivirus (OvLV), like the human immunodeficiency virus (HIV), is a macrophage-tropic lentivirus that leads to persistent, lifelong infection of the host [1,2]
Multidimensional scaling (MDS) identified 3 clusters corresponding to breed, and 15 animals were eliminated for outlier status (Figure S1)
Those mutations did not confer complete resistance, and some flocks with a high frequency of the less susceptible genotypes have high ovine lentivirus (OvLV) prevalence. This genome-wide association study (GWAS) identified multiple additional genomic regions as associated with OvLV susceptibility. This was the first GWAS to examine control of OvLV replication to our knowledge, and multiple genomic regions were identified as associated with control of OvLV replication
Summary
Ovine lentivirus (OvLV), like the human immunodeficiency virus (HIV), is a macrophage-tropic lentivirus that leads to persistent, lifelong infection of the host [1,2]. Mutations in one gene (TMEM154: Transmembrane Protein 154) were identified that contributed to relative susceptibility to OvLV in multiple breed backgrounds and widely differing environmental conditions [16]. The known mutations have not been shown to confer complete resistance to OvLV, and high prevalence has been observed in at least some flocks containing predominantly the less susceptible sheep TMEM154 genotype [16]. These and other genetic variants, once identified, can be used for effective marker-assisted selection even in the absence of pathogen exposure, which could greatly improve animal welfare and economic concerns when breeding for reduced susceptibility to OvLV. The objective here was to identify additional loci associated with odds and/or control of OvLV infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
