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 selective signals observed for TLR3 and TLR8, several tentative associations were detected between bovine TLR SNPs (Table 5 ) and differential susceptibility to MAP infection which have not previously been reported, with one implicated locus (TLR10) also exhibiting evidence of purifying selection (Table 4 ) [30] . However, because the natural ligand(s) for TLR10 have yet to be comprehensively elucidated, the precise origin of this selective signal remains unclear. Previous studies [13, 58] indicate that human TLR10 forms functional heterodimers with both TLR2 and TLR1, thereby enabling the resulting protein complexes to recognize a wide variety of microbial ligands [58] , including those derived from Mycobacteria [11, 12, 14, 59] . Similarly, TLR2 is also known to form functional heterodimers with TLR6 [14] . Recently, AA substitutions in human TLR1 and TLR10 were demonstrated to negatively impact receptor function [58] [59] , with TLR10 ligand recognition similar to the known range of ligands established for TLR1 [58] . The results of our single marker association tests indirectly support the biological concept of functional unity with respect to bovine TLR2, TLR6, and TLR10, with variation at all three loci categorically linked to a common microbial phenotype (bacterial culture status for MAP) in Holstein cattle.