Functional adaptation in Toll-like receptors of wild and domesticated animals
Animals sense their pathogens through detection of conserved pathogen-associated molecules by pattern-recognition receptors (PRRs). The best characterised family of PRRs is the Toll-like receptors. TLR subfamilies retain specificity for particular agonist classes over great evolutionary distances. T...
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| Other Authors: | , |
| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://doi.org/10.5287/ora-da2ormpmd https://ora.ox.ac.uk/objects/uuid:9b3c5d34-17e3-41ad-bcd0-738e85e69aa1 |
| Summary: | Animals sense their pathogens through detection of conserved pathogen-associated molecules by pattern-recognition receptors (PRRs). The best characterised family of PRRs is the Toll-like receptors. TLR subfamilies retain specificity for particular agonist classes over great evolutionary distances. This does not, however, mean that TLRs are evolutionarily static. TLRs, along with other pathogen-facing immune genes, frequently undergo directional selection to maintain leverage in the perpetual arms race between hosts and pathogens. In this thesis, I argue that TLRs are critical determinants of disease susceptibility and resistance, and are therefore under strong selective pressures. To support this, I provide evidence of adaptive evolution operating over multiple nested timescales. For instance, I show that, even in the few thousand years since the domestication of chickens, TLRs have undergone adaptation, likely to better deal with higher pathogen loads in denser, commercialised populations. At the other extreme (hundreds of millions of years), I document the repurposing of the CpG-DNA-recognising TLR21 between fishes and birds, arguing that this compensated for the loss of the unrelated CpG-recognising TLR9 in the birds and reptiles. To contextualise and reinforce my bioinformatic findings, I provide evidence from laboratory experiments to confirm changes in TLR function. For instance, I demon- strate that two positively selected sites in Gentoo penguin TLR5 are sufficient to change the responsiveness of the receptor to its agonist, flagellin. Furthermore, I demonstrate that the ancestor to the Eudyptes (crested) penguins had a cryptic pseu- dogene for TLR15 that was then overtly pseudogenised several independent times in the genus. Functional evidence was crucial in both of these conclusions, and neither could have been deduced from bioinformatic methods alone. Taken together, this body of work provides several lines of evidence that TLRs are key targets for natural selection across multiple evolutionary ... |
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