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Spatial patterns of variation due to natural selection in humans

Key Points

  • Marked geographic patterns for the distribution of some heritable traits are observed in humans, including traits related to disease risk, pathogen resistance and drug response. In some cases, the geographic patterns may be due to natural selection, as shown by correlations between traits and environmental variables (for example, correlations between skin pigmentation and latitude).

  • Spatial patterns of adaptive genetic variation are informative about selective processes. For example, during the spread of an advantageous allele, one can transiently observe 'wave of advance' patterns, or if spatial selection pressures vary across space, stable correlations of allele frequency with environmental variables may be generated.

  • Spatial patterns of neutral variation are also influenced by demographic history. Because some of these genome-wide features may resemble signals of selection, it is important to incorporate information on background spatial patterns of variation when assessing the evidence for adaptations.

  • The extent of allele frequency differentiation across populations can be summarized by the FST statistic. The excess of highly differentiated alleles seen in humans has been interpreted as an effect of positive selection driving diversification between populations.

  • High FST values may also be due to background selection. Because background selection is likely to act more strongly in genic then in non-genic regions, negative rather than positive selection could account for part or all of the observed excess of high FST for genic relative to non-genic SNPs.

  • If selection is strong, targets of local adaptations are expected to have extreme levels of differentiation relative to neutral loci. Accordingly, several variants that confer locally advantageous phenotypes exhibit unusually high levels of allele frequency differences across populations.

  • In natural populations of many species, several quantitative traits are distributed clinally, which mirrors the selective pressures acting on the phenotypes. This observation is consistent with the idea that adaptive genetic variants are also correlated with geographic or environmental variables.

  • Clines of allele frequencies with latitude have been observed for several hypertension susceptibility variants. Moreover, polymorphisms in candidate genes for metabolic syndrome were found to be correlated with climate variables, which is consistent with the hypothesis that spatial patterns of variation are influenced by selective pressures related to thermal stress.

  • Spatial population structure seems to limit the spread of advantageous alleles in humans. Therefore novel mutations and/or standing variation may be more important sources of adaptive variation at a continental scale than the arrival of adaptive alleles through dispersal.

Abstract

Empowered by technology and sampling efforts designed to facilitate genome-wide association mapping, human geneticists are now studying the geography of genetic variation in unprecedented detail. With high genomic coverage and geographic resolution, these studies are identifying loci with spatial signatures of selection, such as extreme levels of differentiation and correlations with environmental variables. Collectively, patterns at these loci are beginning to provide new insights into the process of human adaptation. Here, we review the challenges of these studies and emerging results, including how human population structure has influenced the response to novel selective pressures.

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Figure 1: The 'wave of advance' spread of a globally advantageous mutation.
Figure 2: Spatially varying selection and stable polymorphisms.
Figure 3: Neutral scenarios that produce clines in allele frequencies.
Figure 4: Outlier approaches for identifying candidate targets of selection.
Figure 5: Correlation of a SNP in the RPTOR gene with environmental variables.

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Acknowledgements

We would like to thank M. Przeworski, G. Coop and members of our laboratories for discussions and critical comments on the manuscript. A.D. acknowledges research support from the US National Institutes of Health (GM79558 and DK56670) and J.N. acknowledges support from the Searle Scholars Program and the US National Science Foundation (0733033).

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Glossary

Isolation by distance

A model in which the amount of gene flow between two locations decreases as a function of distance. At equilibrium, this model predicts that genetic differentiation increases as a function of geographic distance. Sometimes the term refers simply to this emergent pattern, rather than the model.

Secondary contact

When two populations that have ceased to exchange migrants begin to re-exchange migrants with one another. In cases in which the populations exchange migrants along a frontier, this boundary is known as a secondary contact zone.

Gene flow

The movement of genes among populations. Often expressed as the proportion of gene copies (or breeding individuals) that are immigrants from a different population.

Serial-founder model

A model of how novel habitats are colonized in which a source population is first sub-sampled to choose founders who will colonize a neighbouring unoccupied space. This sub-sampling process, which results in a population bottleneck, is repeated sequentially as the population further expands into unoccupied space.

Genetic drift

The fluctuations in allele frequency through time that occur owing to chance.

Variance

A measure of the dispersion of a random variable around its mean value.

Coalescent simulation

An efficient and flexible approach for simulating population genetic data. Ancestral lineages are traced backwards in time, and events in which ancestral lineages have common ancestors (coalescent events) are recorded.

Power

The frequency with which a statistical test rejects the null hypothesis given an alternative hypothesis.

Multiple-testing correction

When many statistical tests are conducted simultaneously, some tests are expected to have low p-values under the null hypothesis, and therefore a correction is necessary to compensate for this effect.

Island model

A model of population structure in which several island populations exchange migrants symmetrically.

Purifying selection

When natural selection removes novel deleterious mutations from a population.

Effective population size

The population size needed to predict how a locus would evolve (in accordance with the idealized Wright–Fisher model of population genetics) with respect to a property (typically genetic drift). In many complex scenarios, the behaviour of a locus can be predicted with an appropriate effective population size.

Metabolic syndrome

A combination of traits related to type 2 diabetes, obesity, hypertension and altered lipid levels. It is a major risk factor for cardiovascular disease.

Selective sweep

When a mutation with a beneficial fitness effect arises in a population, natural selection will rapidly increase the frequency of the mutation to a high frequency (partial sweep) or to fixation (complete sweep), which results in a reduction of diversity at and around the selected locus.

RPTOR

(Regulatory-associated protein of mammalian target of rapamycin). The complex between the RPTOR gene product and the target of rapamycin is the central component of a nutrient- and hormone-sensitive signalling pathway that regulates cell growth.

Genetic heterogeneity

The production of a similar phenotype by different mutations at either the same locus or different loci in different individuals.

Linkage disequilibrium

The non-random association of alleles carried at different loci. If a particular combination of alleles on a chromosome is found more or less frequently than expected (assuming independence among loci), then linkage disequilibrium is said to exist. It can arise for various reasons (novel mutations, genetic drift, natural selection and admixture) but recombination is the main process that removes it.

Convergent evolution

The evolution of similar traits by independent processes in individuals with no common ancestry. It usually indicates evolutionary adaptation to similar environmental conditions.

Triple-negative breast cancer

A subtype of breast cancer in which cells lack the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Although breast cancer overall is more common among women of European ancestry, triple-negative cases occur more frequently in post-menopausal women of African ancestry. These cancers are also more aggressive and resistant to current treatment than those that express these receptors.

Salt-sensitive hypertension

Inter-individual variation in blood pressure changes in response to high or low sodium intake. Hypertensive subjects whose blood pressure increases more than a specified proportion upon salt loading are defined as salt sensitive.

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Novembre, J., Di Rienzo, A. Spatial patterns of variation due to natural selection in humans. Nat Rev Genet 10, 745–755 (2009). https://doi.org/10.1038/nrg2632

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