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PMID: 19609346 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense.

PLoS genetics ·Vol. 5 ·No. 7 ·2009-07-00 ·Pages e1000562

Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcaïs A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L

Abstract

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs -- activated by nucleic acids and particularly specialized in viral recognition -- have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface -- activated by compounds other than nucleic acids -- have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.

MeSH Terms
Ethnicity/genetics Evolution, Molecular Genetics, Population Humans Immunity/genetics Infections/immunology Kinetics Mutation Selection, Genetic Sequence Analysis, DNA Toll-Like Receptors/genetics,immunology
Chemicals
Toll-Like Receptors
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Barreiro Luis B
Institut Pasteur, Human Evolutionary Genetics, CNRS, URA3012, Paris, France.
Ben-Ali Meriem
Quach Hélène
Laval Guillaume
Patin Etienne
Pickrell Joseph K
Bouchier Christiane
Tichit Magali
Neyrolles Olivier
Gicquel Brigitte
Kidd Judith R
Kidd Kenneth K
Alcaïs Alexandre
Ragimbeau Josiane
Pellegrini Sandra
Abel Laurent
Casanova Jean-Laurent
Quintana-Murci Lluís
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000562
Published
2009-07-00
Epub
2009-00-17
Pages
e1000562
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2702086
Subset
IM
Grants
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1000562 PMC Full Text View journal details
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