Evolution of the bovine TLR gene family and member associations with Mycobacterium avium subspecies paratuberculosis infection

• Published in: PloS one Vol. 6; no. 11; p. e27744
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30-11-2011; Public Library of Science (PLoS)
• Subjects: Algorithms; Amino acids; Animal sciences; Animals; Bacteria; Bayesian analysis; Biology; Bos taurus indicus; Bos taurus taurus; Cattle; Cattle Diseases - genetics; Cattle Diseases - immunology; Cattle Diseases - microbiology; Dairy cattle; Deoxyribonucleic acid; Disease; Disease susceptibility; DNA; Epidemiology; Evolution; Evolution, Molecular; Gene Frequency; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Genomes; Genomics; Genotype; Genotyping; Haplotypes; Host-Pathogen Interactions - immunology; Hybrids; Immune response; Immune system; INDEL Mutation; Infections; Innate immunity; Insertion; Johne's disease; Ligands; Linkage disequilibrium; Mammals; Medicine; Multigene Family; Mutation; Mycobacterium avium; Mycobacterium avium subsp. paratuberculosis - immunology; Mycobacterium avium subsp. paratuberculosis - physiology; Odds Ratio; Paratuberculosis; Paratuberculosis - genetics; Paratuberculosis - immunology; Paratuberculosis - microbiology; Polymorphism; Polymorphism, Single Nucleotide; Population; Proteins; Residential density; Signal transduction; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Testing laboratories; TLR3 protein; Toll-Like Receptor 10 - genetics; Toll-Like Receptor 10 - immunology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 6 - genetics; Toll-Like Receptor 6 - immunology; Toll-like receptors; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Trends; Tuberculosis; Vaccination; Veterinary colleges; Veterinary medicine; Veterinary Science; United States > US; Texas; Missouri
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027744

Members of the Toll-like receptor (TLR) gene family occupy key roles in the mammalian innate immune system by functioning as sentries for the detection of invading pathogens, thereafter provoking host innate immune responses. We utilized a custom next-generation sequencing approach and allele-specific genotyping assays to detect and validate 280 biallelic variants across all 10 bovine TLR genes, including 71 nonsynonymous single nucleotide polymorphisms (SNPs) and one putative nonsense SNP. Bayesian haplotype reconstructions and median joining networks revealed haplotype sharing between Bos taurus taurus and Bos taurus indicus breeds at every locus, and specialized beef and dairy breeds could not be differentiated despite an average polymorphism density of 1 marker/158 bp. Collectively, 160 tagSNPs and two tag insertion-deletion mutations (indels) were sufficient to predict 100% of the variation at 280 variable sites for both Bos subspecies and their hybrids, whereas 118 tagSNPs and 1 tagIndel predictively captured 100% of the variation at 235 variable sites for B. t. taurus. Polyphen and SIFT analyses of amino acid (AA) replacements encoded by bovine TLR SNPs indicated that up to 32% of the AA substitutions were expected to impact protein function. Classical and newly developed tests of diversity provide strong support for balancing selection operating on TLR3 and TLR8, and purifying selection acting on TLR10. An investigation of the persistence and continuity of linkage disequilibrium (r2≥0.50) between adjacent variable sites also supported the presence of selection acting on TLR3 and TLR8. A case-control study employing validated variants from bovine TLR genes recognizing bacterial ligands revealed six SNPs potentially eliciting small effects on susceptibility to Mycobacterium avium spp paratuberculosis infection in dairy cattle. The results of this study will broadly impact domestic cattle research by providing the necessary foundation to explore several avenues of bovine translational genomics, and the potential for marker-assisted vaccination.