Review Article | Published:

Natural selection and infectious disease in human populations

Nature Reviews Genetics volume 15, pages 379393 (2014) | Download Citation

Abstract

The ancient biological 'arms race' between microbial pathogens and humans has shaped genetic variation in modern populations, and this has important implications for the growing field of medical genomics. As humans migrated throughout the world, populations encountered distinct pathogens, and natural selection increased the prevalence of alleles that are advantageous in the new ecosystems in both host and pathogens. This ancient history now influences human infectious disease susceptibility and microbiome homeostasis, and contributes to common diseases that show geographical disparities, such as autoimmune and metabolic disorders. Using new high-throughput technologies, analytical methods and expanding public data resources, the investigation of natural selection is leading to new insights into the function and dysfunction of human biology.

Key points

  • Infectious pathogens are among the strongest selective forces that shape the human genome. Migrations and cultural changes in the past 100,000 years exposed populations to dangerous new pathogens.

  • Host genetics influences susceptibility to infectious disease. Evolutionary adaptations for resistance and symbiosis may underlie common immune-mediated diseases.

  • Signatures of selection and methods to detect them vary with the age, geographical spread and virulence of the pathogen.

  • A history of selection on a trait adds power to association studies by driving the emergence of common alleles of strong effect. Combining selection and association metrics can further increase power.

  • Genome-wide association studies (GWASs) of susceptibility to pathogens that are moderately old (1,000–50,000 years ago), geographically limited in history and exerted strong positive selective pressure will have the most power if GWASs can be done in the historically affected population.

  • An understanding of host–pathogen interactions can inform the development of new therapies for both infectious diseases and common immune-mediated diseases.

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Acknowledgements

The authors thank S. Schaffner, E. Brown, D. Park, D. Neafsey, R. LaRocque and J. Harris for discussions.

Author information

Affiliations

  1. Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Elinor K. Karlsson
    •  & Pardis C. Sabeti
  2. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.

    • Elinor K. Karlsson
    •  & Pardis C. Sabeti
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

    • Dominic P. Kwiatkowski
  4. Wellcome Trust Sanger Centre for Human Genetics, Oxford OX3 7BN, UK.

    • Dominic P. Kwiatkowski
  5. Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Pardis C. Sabeti

Authors

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Elinor K. Karlsson or Pardis C. Sabeti.

Supplementary information

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    Supplementary information S1 (table)

    Pathogen GWASs in NHGRI GWAS catalog (https://www.genome.gov/26525384) as of April 15, 2014

Glossary

Pathogens

Viruses, bacteria or other microorganisms that can cause disease.

Signatures of selection

An unusual pattern of allele frequencies that marks a selected locus.

Frequency

Prevalence of an allele in a population.

Genome-wide association studies

(GWASs). Examination of variants that are distributed across the entire genome for correlation with particular traits.

Next-generation sequencing

New high-throughput, parallelized, low-cost sequencing technologies that do not use the chain termination Sanger method.

Genetic diversity

Total amount of genetic variation in a population.

Bottlenecks

Sharp decreases in the effective sizes of populations.

Admixture

Interbreeding between two genetically separated populations.

Ascertainment bias

Nonrandom selection of variants for genotyping.

Neutral variation

Genetic variation that confers no selective advantage or disadvantage and that varies in frequency by random drift.

Linkage disequilibrium

(LD). The nonrandom association of alleles at different genomic loci.

Fixation

The increase in frequency of an allele to 100% in a population.

Standing variation

Existing genetic variation within a population.

Selective sweeps

Reductions in genetic variation caused by positive selection at particular loci.

Incomplete sweeps

Partial or ongoing selective sweeps of advantageous alleles to <100% prevalence.

Complete sweeps

Selective sweeps of advantageous alleles to 100% prevalence.

Candidate gene approach

Association study that tests only variants in a pre-specified set of genes.

Pathway-based approaches

Methods that test for joint association of genes in the same functional pathway.

Expression quantitative trait loci

(eQTLs). Genomic loci that regulate gene expression.

Imputation

Statistical prediction of missing genetic data.

Gene set enrichment

Overrepresentation of an a priori defined group of genes.

Pleiotropic effects

Effects on multiple unrelated phenotypes.

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DOI

https://doi.org/10.1038/nrg3734

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