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  • Review Article
  • Published:

Signatures of natural selection in the human genome

Nature Reviews Genetics volume 4, pages 99–110 (2003)Cite this article

Key Points

  • Natural selection leaves signatures in our genome that can be used to identify the genes that might underlie variation in disease resistance or drug metabolism.

  • Signatures of natural selection are confounded by population history and variation in local recombination rates.

  • Demographic processes should affect all loci in a similar way, whereas the effects of selection should be restricted to specific loci.

  • Selection might have been more important in shaping patterns of variation in the genome than was previously anticipated, although the relative importance of background selection and genetic hitchhiking remains unknown.

  • Most strategies that are used to detect whether natural selection has affected a specific allele measure the departure of the allele's frequency from expectations under a neutral model.

  • Evidence of positive selection acting on genes is beginning to accumulate.

  • Many coding regions in the human genome do not show an excess of low-frequency alleles. This indicates that balancing selection might be more common than generally perceived.

  • The wealth of nucleotide polymorphism data that has become available during the past few years has provided an exciting opportunity to carry out genome scans for selection.

  • Continued progress towards identifying genes that are subject to selection will depend on understanding more about the demographic structure of human populations.

  • Even after a candidate locus has been shown to be subject to selection, it will require a substantial amount of work to identify the causal variants and to understand its relationship to a human phenotype.

Abstract

During their dispersal from Africa, our ancestors were exposed to new environments and diseases. Those who were better adapted to local conditions passed on their genes, including those conferring these benefits, with greater frequency. This process of natural selection left signatures in our genome that can be used to identify genes that might underlie variation in disease resistance or drug metabolism. These signatures are, however, confounded by population history and by variation in local recombination rates. Although this complexity makes finding adaptive polymorphisms a challenge, recent discoveries are instructing us how and where to look for the signatures of selection.

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Figure 1: Effects of natural selection on gene genealogies and allele frequencies.
Figure 2: The effects of selection on the distribution of genetic variation.
Figure 3: Using phylogenetic techniques to infer haplotype structure.
Figure 4: Detecting recent positive selection using linkage disequilibrium analysis.
Figure 5: Screening the human genome for signatures of natural selection.

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Acknowledgements

We thank L. B. Jorde, A. R. Rogers and three anonymous reviewers for comments and criticisms. The authors are supported by funds from the US National Institutes of Health and the National Science Foundation.

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Authors and Affiliations

  1. Department of Human Genetics, University of Utah, Salt Lake City, 84112, Utah, USA

    Michael Bamshad & Stephen P. Wooding

  2. Department of Pediatrics, University of Utah, Salt Lake City, 84112, Utah, USA

    Michael Bamshad

Authors
  1. Michael Bamshad
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  2. Stephen P. Wooding
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Correspondence to Michael Bamshad or Stephen P. Wooding.

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DATABASES

LocusLink

BRCA1

calpain-10

CCR5

CYP1A2

DRD4

G6PD

MAOA

MC1R

PPARG

OMIM

idiopathic haemochromatosis

type II diabetes

Glossary

FITNESS

The ability of an individual to reproduce his or her genetic makeup, which is not always equivalent to individual reproductive success.

FIXATION

The increase in the frequency of a genetic variant in a population to 100%.

BALANCING SELECTION

A selection regime that results in the maintenance of two or more alleles at a single locus in a population.

BACKGROUND SELECTION

The elimination of neutral polymorphisms as a result of the negative selection of deleterious mutations at linked sites.

POLYMORPHISM

The contemporary definition refers to any site in the DNA sequence that is present in the population in more than one state. By contrast, the traditional definition referred to an allele with a population frequency >1% and <99%.

GENETIC DRIFT

The random fluctuations of allele frequencies over time due to chance alone.

GENETIC LOAD

The proportion of a population's maximum fitness that is lost as a result of selection against the deleterious genotypes it contains.

EFFECTIVE POPULATION SIZE

The size of the ideal population in which the effects of random drift would be the same as those seen in the actual population.

POPULATION STRUCTURE

A departure from random mating as a consequence of factors such as inbreeding, overlapping generations, finite population size and geographical subdivision.

SELECTIVE SWEEP

The process by which positive selection for a mutation eliminates neutral variation at linked sites.

STANDARD NEUTRAL MODEL

A hypothetical panmictic (randomly mating) population of constant size in which genetic variation is neutral and follows a model (the 'infinite sites model') in which each new mutation occurs at a site that has not previously mutated.

VARIANCE

A statistic that quantifies the dispersion of data about the mean.

MINOR ALLELE

The less frequent of two alleles at a locus.

OUTGROUP

A closely related species that is used for comparison, for example, to infer the ancestral versus the derived state of a polymorphism.

LIKELIHOOD ANALYSIS

A statistical method that calculates the probability of the observed data under varying hypotheses, in order to estimate model parameters that best explain the observed data and determine the relative strengths of alternative hypotheses.

PHYLOGENETICS

Reconstruction of the evolutionary relationships (that is, the phylogeny) of a group of taxa, such as species.

LINKAGE DISEQUILIBRIUM

(LD). The non-random association of alleles in haplotypes.

HAPLOTYPE

The combination of alleles or genetic markers found on a single chromosome of a given individual.

SITE FREQUENCY SPECTRUM

The fraction of polymorphic sites at which a minor or derived allele is present in one copy, two copies and so on.

SINGLE-LINKAGE JOINING ALGORITHM

A simple clustering algorithm that begins with all data points (for example, haplotypes) in separate clusters, and then iteratively joins pairs of similar clusters.

DUFFY BLOOD GROUP

This group is defined by variants in a chemokine receptor that is present on the surface of several types of cell, including red blood cells. This receptor must be present for Plasmodium vivax to invade cells and cause malaria.

WRIGHT'S FIXATION INDEX

(FST). The fraction of the total genetic variation that is distributed among subpopulations in a subdivided population.

2 × 2 CONTINGENCY TABLE

A 2 × 2 table that describes the cross-classification of data that are divided into two groups with two categories in each.

EPISTATIC

An interaction between non-allelic genes, such that one gene masks, interferes with or enhances the expression of the other gene.

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Bamshad, M., Wooding, S. Signatures of natural selection in the human genome. Nat Rev Genet 4, 99–110 (2003). https://doi.org/10.1038/nrg999

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