Evidence for polygenic adaptation to pathogens in the human genome

Most approaches aiming at finding genes involved in adaptive events have focused on the detection of outlier loci, which resulted in the discovery of individually "significant" genes with strong effects. However, a collection of small effect mutations could have a large effect on a given b...

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Bibliographic Details
Published in:Molecular biology and evolution 2013-07, Vol.30 (7), p.1544-1558
Main Authors: Daub, Josephine T, Hofer, Tamara, Cutivet, Emilie, Dupanloup, Isabelle, Quintana-Murci, Lluis, Robinson-Rechavi, Marc, Excoffier, Laurent
Format: Article
Language:English
Subjects:
Adaptation, Biological
Bacteria
Epistasis, Genetic
Genes
Genome, Human
Genomes
Genotype
Genotype & phenotype
Host-Pathogen Interactions - genetics
Human populations
Humans
Immune response
Linkage Disequilibrium
Metabolic Networks and Pathways
Models, Theoretical
Multifactorial Inheritance - genetics
Mutation
Pathogens
Polymorphism, Single Nucleotide
Selection, Genetic - genetics
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Summary:Most approaches aiming at finding genes involved in adaptive events have focused on the detection of outlier loci, which resulted in the discovery of individually "significant" genes with strong effects. However, a collection of small effect mutations could have a large effect on a given biological pathway that includes many genes, and such a polygenic mode of adaptation has not been systematically investigated in humans. We propose here to evidence polygenic selection by detecting signals of adaptation at the pathway or gene set level instead of analyzing single independent genes. Using a gene-set enrichment test to identify genome-wide signals of adaptation among human populations, we find that most pathways globally enriched for signals of positive selection are either directly or indirectly involved in immune response. We also find evidence for long-distance genotypic linkage disequilibrium, suggesting functional epistatic interactions between members of the same pathway. Our results show that past interactions with pathogens have elicited widespread and coordinated genomic responses, and suggest that adaptation to pathogens can be considered as a primary example of polygenic selection.
ISSN:0737-4038
1537-1719
DOI:10.1093/molbev/mst080