Key Points
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Pathogens and infectious diseases have been, and still are, paramount among the threats to human health and survival. Exposure to infection has therefore imposed strong selective pressures on the evolution of the human genome.
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The field of evolutionary genetics of immunity searches the genome of present-day human populations for molecular 'footprints' of natural selection that have been exerted by past infections.
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Some of the strongest evidence of selection in the human genome has been obtained for genes involved in immunity and host defence, as revealed by genome-wide scans for selection among primate species and within human populations.
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Evolutionary genetics reveal genes that have a redundant role in host defence and show how, in certain circumstances, recent gene loss can represent a selective advantage for the host.
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The signatures of positive selection observed at some disease-associated SNPs suggest that the increasing prevalence of autoimmune disorders in modern societies might, at least partially, be the consequence of past selective events to combat infection.
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Characterizing how natural selection has targeted immunity-related genes provides important clues for delineating human genes and immunological pathways that have major roles in host defence and for predicting which regions of the genome are associated with susceptibility to infection or disease outcome.
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Integrative approaches that combine evolutionary genetics data with immunological phenotypes will help to elucidate more precisely the immunological mechanisms that have been targeted by natural selection in humans.
Abstract
Pathogens have always been a major cause of human mortality, so they impose strong selective pressure on the human genome. Data from population genetic studies, including genome-wide scans for selection, are providing important insights into how natural selection has shaped immunity and host defence genes in specific human populations and in the human species as a whole. These findings are helping to delineate genes that are important for host defence and to increase our understanding of how past selection has had an impact on disease susceptibility in modern populations. A tighter integration between population genetic studies and immunological phenotype studies is now necessary to reveal the mechanisms that have been crucial for our past and present survival against infection.
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Acknowledgements
We would like to thank L. Abel, M. Ben-Ali, J. L. Casanova, Y. Gilad, B. Jabri, O. Neyrolles, E. Patin, G. Perry, M. Przeworski, H. Quach and P. Sansonetti for helpful comments and discussions, and J. Akey, M. Carrington and R. Single for sharing data that helped the writing of this Review. L.B.B. is supported by a Human Frontier Science Program postdoctoral fellowship. This work was supported by the Institut Pasteur, the Centre National de la Recherche Scientifique, the Fondation pour la Recherche Médicale, and an Agence Nationale de la Recherche research grant (ANR-08-MIEN-009-01) to L.Q.-M.
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Supplementary information
Supplementary Table 1
List of immunity-related genes reported to be rapidly evolving in the human-lineage, in the chimpanzee-lineage, or in both. (XLS 58 kb)
Supplementary Table 2
List of immunity-related genes presenting signatures of recent positive selection as revealed by at least one genome-wide scan for selection. (XLS 118 kb)
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Supplementary Note (PDF 266 kb)
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FURTHER INFORMATION
Lluís Quintana-Murci's laboratory
Human Genome Diversity Project selection browser
Innate Immunity Program in Genomics Applications
National Human Genome Research Institute catalogue of published GWA studies
National Institute of Environmental Health Sciences Environmental Genome Project
Glossary
- Innate immunity
-
Non-specific and evolutionarily ancient mechanisms that form the first line of host defence against infection. Innate immunity, which is inborn and does not involve memory, provides immediate defence and is found in all classes of plants and animals.
- Adaptive immunity
-
A highly adaptable and specific immune response that can adjust to new pathogens (structures) and that retains a memory of prior exposure to them. Thought to have arisen in jawed vertebrates, the adaptive immune system is stimulated by the innate immune system.
- McDonald–Kreitman test
-
The McDonald–Kreitman test compares the ratio of polymorphism (within-species variation) to divergence (between-species variation) at non-synonymous and synonymous sites.
- Gene Ontology
-
A widely used classification system of gene functions and other gene attributes that uses a controlled vocabulary. The ontology covers three domains; cellular components, molecular functions and biological processes.
- Simian immunodeficiency virus
-
A type of retrovirus found in African non-human primates. Unlike HIV infections in humans, simian immunodeficiency virus infections in their natural hosts are usually non-pathogenic.
- Copy-number variation
-
A class of DNA sequence variant (including deletions and duplications) in which the result is a departure from the expected diploid representation of DNA sequence.
- Erythrocyte
-
A cell that contains haemoglobin and that can carry oxygen to the body. They are also known as red blood cells.
- Antigen
-
Any substance that the immune system can respond to by producing antibodies.
- Linkage disequilibrium
-
The non-random association of alleles at two or more loci. The pattern of linkage disequilibrium in a genomic region is affected by mutation, recombination, genetic drift, natural selection and demographic history.
- Genetic hitchhiking
-
The process by which a neutral, or in some cases deleterious, mutation may increase in population frequency owing to linkage with a positively selected mutation.
- Outlier approaches
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Popular approaches for detecting selection that identify loci that present extreme values for a given statistic from empirical genome-wide genetic data. It is assumed that these 'outlier loci' are enriched for loci targeted by selection.
- Interleukins
-
A group of secreted proteins that are produced by immune cells and that can modulate immune and inflammatory responses.
- Fixation
-
The increase in the frequency of a genetic variant in a population to 100%.
- Haplotype
-
The allelic composition over a contiguous chromosome stretch.
- Complement pathway
-
The complement system is a complex protein cascade that is involved in both innate and adaptive immunity. Three pathways activate the complement system: the classical pathway, the alternative pathway and the lectin pathway.
- Ficolins
-
A group of humoral proteins that contain a collagen-like domain and a fibrinogen-like domain. They can bind carbohydrate molecules on pathogens, apoptotic and necrotic cells to activate the lectin complement pathway.
- Caspases
-
Enzymes that play an important part in the immune system by activating numerous cellular proteins that are involved in apoptosis, necrosis, immunity and inflammation. They are synthesized as inactive procaspases that are later activated by proteolytic cleavage into active caspases.
- Fitness
-
A measure of the capacity of an organism to survive and reproduce.
- Leprosy reversal reaction
-
A syndrome that is characterized by the rapid activation of a T helper 1 inflammatory response to Mycobacterium leprae. This reaction can cause substantial morbidity.
- Genome-wide association studies
-
Studies in which associations between genetic variation and a phenotype or trait of interest are identified by genotyping cases (for example, diseased individuals) and controls (for example, healthy individuals) for a set of genetic variants that capture variation across the entire genome.
- Expression quantitative trait loci
-
Regions of the genome at which genetic allelic variation is associated with variation in gene expression.
- Quantitative trait loci
-
Regions of the genome at which genetic variation is associated with a particular phenotypic characteristic or trait (for example, height, weight or skin colour).
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Barreiro, L., Quintana-Murci, L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11, 17–30 (2010). https://doi.org/10.1038/nrg2698
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DOI: https://doi.org/10.1038/nrg2698
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