|HERRMANN-HOESING, LYNN - Washington State University|
|NEIBERGS, HOLLY - Washington State University|
|Knowles Jr, Donald|
Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/17/2012
Publication Date: 10/17/2012
Citation: White, S.N., Mousel, M.R., Herrmann-Hoesing, L.M., Reynolds, J.O., Leymaster, K.A., Neibergs, H.L., Lewis, G.S., Knowles Jr, D.P. 2012. Genome-Wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus. PLoSOne 7(10):e47829.
Interpretive Summary: Like human immunodeficiency virus, ovine lentivirus (OvLV) targets macrophage cells in the immune system and causes lifelong infection. OvLV infects approximately one quarter of U.S. sheep and induces varying degrees of pneumonia and body condition wasting. Thus, OvLV is also known as ovine progressive pneumonia virus. There is no vaccine to prevent OvLV infection, and there is no cost-effective treatment for infected animals. However, some breeds have consistently lower prevalence and less control of viral replication when infected than others, indicating a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 as an important gene in OvLV susceptibility, but complete resistance was not observed and contorl of viral replication of infection was not examined. Therefore, we performed a larger genome-wide association scan to search for more genes involved in probability and severity of OvLV infection. This study confirmed the association of TMEM154, and added several additional genes associated with both probability of infection and control of OvLV infection. To our knowledge, none of these additional genes had been previously associated with any lentiviral infection in any mammal. These results provide targets for mutation discovery and eventual selective breeding of sheep to reduce susceptibility to OvLV. The genes may also be useful for further study of goat susceptibility to the closely related caprine arthritis encephalitis virus.
Technical Abstract: Background: Like human immunodeficiency virus (HIV), ovine lentivirus (OvLV) is macrophage-tropic and causes lifelonginfection. 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 Findings: This 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 = 9.261027; 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, 161025). 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/Significance: These 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.