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Divergent cis-regulatory haplotypes at Tlr2 are associated with immune responsiveness

Nandakumar, Mridula LU orcid ; Lundberg, Max LU ; Nouri, Mehrnaz LU ; Valfridsson, Christine LU ; Carlsson, Fredric LU orcid and Råberg, Lars LU (2026) In Molecular biology and evolution 43(5).
Abstract

Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to target ligand-binding domains and affect the specificity of recognition of different pathogens. Alternatively, positive/balancing selection on PRRs could affect general responsiveness by targeting for example signaling domains or cis-regulatory variation. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate what aspect of TLR2 function has been under selection, we here perform integrated... (More)

Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to target ligand-binding domains and affect the specificity of recognition of different pathogens. Alternatively, positive/balancing selection on PRRs could affect general responsiveness by targeting for example signaling domains or cis-regulatory variation. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate what aspect of TLR2 function has been under selection, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the phylogenetically distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is 4.6 kb upstream of the Tlr2 CDS, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively, these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via TLR2 signaling rather than on polymorphisms affecting TLR2 ligand-binding specificity.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
allelic imbalance, evolutionary immunology, Myodes glareolus, pathogen-mediated selection, Toll-like receptor
in
Molecular biology and evolution
volume
43
issue
5
article number
msag113
publisher
Oxford University Press
external identifiers
  • scopus:105040360618
  • pmid:42052896
ISSN
0737-4038
DOI
10.1093/molbev/msag113
language
English
LU publication?
yes
id
b891f19f-bc3a-46a0-b003-0c908749f727
date added to LUP
2026-09-04 14:57:30
date last changed
2026-09-18 15:43:07
@article{b891f19f-bc3a-46a0-b003-0c908749f727,
  abstract     = {{<p>Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to target ligand-binding domains and affect the specificity of recognition of different pathogens. Alternatively, positive/balancing selection on PRRs could affect general responsiveness by targeting for example signaling domains or cis-regulatory variation. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2—a lipoprotein-binding PRR—is highly polymorphic with divergent haplotypes and signatures of balancing selection and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate what aspect of TLR2 function has been under selection, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the phylogenetically distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is 4.6 kb upstream of the Tlr2 CDS, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively, these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via TLR2 signaling rather than on polymorphisms affecting TLR2 ligand-binding specificity.</p>}},
  author       = {{Nandakumar, Mridula and Lundberg, Max and Nouri, Mehrnaz and Valfridsson, Christine and Carlsson, Fredric and Råberg, Lars}},
  issn         = {{0737-4038}},
  keywords     = {{allelic imbalance; evolutionary immunology; Myodes glareolus; pathogen-mediated selection; Toll-like receptor}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{Oxford University Press}},
  series       = {{Molecular biology and evolution}},
  title        = {{Divergent cis-regulatory haplotypes at Tlr2 are associated with immune responsiveness}},
  url          = {{http://dx.doi.org/10.1093/molbev/msag113}},
  doi          = {{10.1093/molbev/msag113}},
  volume       = {{43}},
  year         = {{2026}},
}