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 view of the emerging global interest in genomic selection in beef and dairy cattle, we provide evidence for balancing selection on at least two of the TLR genes (TLR3 and TLR8), with detection of a weaker selective signal consistent with purifying selection in TLR10 [30] (Table 4 ). Interestingly, TLR3 and TLR8 encode molecular sentries that recognize invading double-stranded (ds) and single-stranded (ss) RNA viruses, respectively, thereafter eliciting host innate immune responses (11, 12) . Importantly, selection on TLR3 and TLR8 may have direct implications on aspects of differential susceptibility to major viral production diseases such as bluetongue (dsRNA; Reoviridae), foot and mouth disease (ssRNA; Picornaviridae), bovine viral diarrhea (ssRNA; Flaviviridae), calf coronavirus (ssRNA; neonatal diarrhea; Coronaviridae), and bovine parainfluenza 3 (ssRNA; Paramyxoviridae) (see [55, 56] ). Moreover, evolution under repeated exposure to many of these diseases may provide some explanation for the observed patterns of variation detected within TLR3 and TLR8. However, it is also possible that more ancient host-pathogen interactions (i.e., eradicated Rinderpest, ssRNA, Paramyxoviridae; etc) may have contributed to the signatures of selection detected in this study. It should also be noted that because frequency distribution tests generally lack power to detect selection [51] , departures from neutrality noted in this study are likely to underscore the strength of the selective signals observed (for review see [57] ). For these reasons, future studies involving all species of the subfamily Bovinae are needed to help elucidate whether selective signals in TLR3 and TLR8 extend beyond modern domestic cattle lineages. Moreover, variation within these genes should be comprehensively evaluated with respect to differences in ligand-induced signaling, disease susceptibility, and the potential for marker-assisted vaccination in domestic cattle.