| Title: |
Genetic susceptibility to severe childhood asthma and rhinovirus-C maintained by balancing selection in humans for 150 000 years |
| Authors: |
O'Neill, Mary, B; Laval, Guillaume; Teixeira, Joao; Palmenberg, Ann, C; Pepperell, Caitlin, S |
| Contributors: |
University of Wisconsin-Madison; Génétique Evolutive Humaine - Human Evolutionary Genetics; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); University of Adelaide; National Institutes of Health (1R01AI113287-01A1 to C.S.P.).; We wish to thank Andrew Kitchen for his advice on phylogenetic analyses and Lluis Quintana-Murci and Etienne Patin for feedback on the manuscript |
| Source: |
ISSN: 0964-6906. |
| Publisher Information: |
CCSD; Oxford University Press (OUP) |
| Publication Year: |
2020 |
| Collection: |
Institut Pasteur: HAL |
| Subject Terms: |
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE]; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics |
| Description: |
International audience ; Selective pressures imposed by pathogens have varied among human populations throughout their evolution, leading to marked inter-population differences at some genes mediating susceptibility to infectious and immune-related diseases. Here, we investigated the evolutionary history of a common polymorphism resulting in a Y529 versus C529 change in the cadherin related family member 3 (CDHR3) receptor which underlies variable susceptibility to rhinovirus-C infection and isassociated with severe childhood asthma. The protective variant is the derived allele and is found at high frequency worldwide (69–95%).We detected genome-wide significant signatures of natural selection consistent with a rapid increase of the haplotypes carrying the allele, suggesting that non-neutral processes have acted on this locus across all human populations. However, the allele has not fixed in any population despite multiple lines of evidence suggesting that the mutation predates human migrations out of Africa. Using an approximate Bayesian computation method, we estimate the age of the mutation while explicitly accounting for past demography and positive or frequency-dependent balancing selection. Our analyses indicate a single emergence of the mutation in anatomically modern humans ∼150 000 years ago and indicate that balancing selection has maintained the beneficial allele at high equilibrium frequencies worldwide. Apart from the well-known cases of the MHC and ABO genes, this study provides the first evidence that negative frequency-dependent selection plausibly acted on a human disease susceptibility locus, a form of balancing selection compatible with typical transmission dynamics of communicable respiratory viruses that might exploit CDHR3. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/31841129; PUBMED: 31841129; PUBMEDCENTRAL: PMC7104676 |
| DOI: |
10.1093/hmg/ddz304 |
| Availability: |
https://pasteur.hal.science/pasteur-02882136; https://pasteur.hal.science/pasteur-02882136v1/document; https://pasteur.hal.science/pasteur-02882136v1/file/O%27NEILL_Human%20Molecular%20Genetics%202020.pdf; https://doi.org/10.1093/hmg/ddz304 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.A8410F5B |
| Database: |
BASE |