Evolution of the Bovine TLR Gene Family and Member Associations with Mycobacterium avium Subspecies paratuberculosis Infection

Fisher, Colleen A.; Bhattarai, Eric K.; Osterstock, Jason B.; Dowd, Scot E.; Seabury, Paul M.; Vikram, Meenu; Whitlock, Robert H.; Schukken, Ynte H.; Schnabel, Robert D.; Taylor, Jeremy F.; Womack, James E.; Seabury, Christopher M.

In addition to in silico determined signatures of selection, we also provide evidence for associations between several bovine TLR SNPs and differential susceptibility to the causative agent of Johne's disease (Table 5) . Unlike most previous studies [19] [20] [21] [22] 46] , we detected associations for which TLR variation both enhanced and decreased the risk of MAP infection. Furthermore, the SNPs demonstrating associations in this study (Table 5) were within bovine TLR genes that are either known or postulated to recognize ligands that would facilitate MAP detection and signaling [7, 11, 12, [19] [20] [21] [22] 46, 52] . While two recent genome wide association studies (GWAS) employing the Illumina BovineSNP50 assay provided no evidence for TLR involvement in differential susceptibility to Johne's disease in cattle [53, 54] , the stringency of multiple testing employed during GWAS may have failed to identify TLR loci modulating relatively small effects. Moreover, the marker density of the BovineSNP50 assay is insufficient to detect all possible associations with bovine TLR variation [30] (Table S2) . The SNP density for the new Illumina BovineHD assay also may not be sufficient to detect all disease associations with TLR loci, and therefore, additional association and functional studies are needed to clarify the involvement of TLR2, TLR6, and TLR10 with respect to differential susceptibility to MAP infection in Holstein cattle.