Genomic signatures of selection at linked sites: unifying the disparity among species

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Abstract

Population genetics theory supplies powerful predictions about how natural selection interacts with genetic linkage to sculpt the genomic landscape of nucleotide polymorphism. Both the spread of beneficial mutations and the removal of deleterious mutations act to depress polymorphism levels, especially in low-recombination regions. However, empiricists have documented extreme disparities among species. Here we characterize the dominant features that could drive differences in linked selection among species — including roles for selective sweeps being 'hard' or 'soft' — and the concealing effects of demography and confounding genomic variables. We advocate targeted studies of closely related species to unify our understanding of how selection and linkage interact to shape genome evolution.

Key Points

  • Population genetics theory supplies powerful predictions about how natural selection, interacting with genetic linkage, will sculpt the genomic landscape of nucleotide polymorphism.

  • Genetic hitch-hiking of neutral alleles linked to a beneficial mutation undergoing a 'hard' selective sweep, or the selective removal by background selection of deleterious mutations, will more greatly affect patterns of polymorphism in genomic regions with little recombination.

  • Despite supporting evidence for genetic hitch-hiking and background selection from many organisms, empiricists have documented extreme disparities among species.

  • The dominant features that could drive variation in linked selection among species include the potential roles for selective sweeps being 'hard' or 'soft' and the concealing effects of demography and confounding genomic variables.

  • We advocate targeted studies of closely related species that differ in key variables to help clarify the causes of among-species disparities and to unify our understanding of how selection and linkage interact to shape genome evolution.

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Figure 1: A hypothetical chromosome exhibiting a 'selection at linked sites' pattern.
Figure 2: Modes of selection on linked genetic variation and factors affecting them.
Figure 3: Taxonomic support for different signatures of selection at linked sites.

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Acknowledgements

A.D.C. is supported by grants from the Natural Sciences and Engineering Research Council of Canada, the US National Institutes of Health (NIH) and a Canada Research Chair. B.A.P. is supported by NIH grant HG004498. We thank L. Loewe and three anonymous reviewers for helpful comments.

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Correspondence to Asher D. Cutter.

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The authors declare no competing financial interests.

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Glossary

Directional selection

Selection that favours one allele over all other alleles of a gene. The frequency of this beneficial allele can rise or can be held in check by recurrent mutations.

Selective interference

When recombination fails to break down linkage disequilibrium between alleles at selected loci, the ability of selection to act on these alleles tends to be reduced.

Selection at linked sites

The interaction between natural selection and genetic linkage that can yield deviations from the levels of polymorphism, allele frequencies and linkage disequilibria expected from neutral evolution alone.

Selective sweep

The increase in frequency of a beneficial allele (and closely linked chromosomal segments by genetic hitch-hiking) to fixation that is caused by positive selection.

Genetic hitch-hiking

The process by which a neutral, or in some cases deleterious, mutations may change in population frequency owing to linkage with a selected mutation.

Site frequency spectrum

The distribution of allele frequencies in a population; it is visualized as the histogram of counts of the number of alleles that have a given population frequency.

Effective population size

(Ne). Formulated by Wright in 1931, Ne reflects the size of an idealized population that would experience drift in the same way as the actual (census) population. Ne can be lower than census population size owing to various factors, including variance in reproductive success, a history of population bottlenecks and inbreeding.

Background selection

The elimination of neutral polymorphisms as a result of their linkage to deleterious mutations that are subject to purifying selection.

Neutral polymorphism

Alternative allelic variants with no selective difference between them, the dynamics of which are mainly controlled by genetic drift and migration. They can, however, be influenced by selection on nearby (linked) loci.

Replacement sites

Also known as nonsynonymous sites, these are any nucleotides within a gene at which a point mutation can alter the encoded amino acid sequence. Models of molecular evolution account for different possible degeneracies of such sites in codons.

d N

The rate of protein-coding sequence divergence that is quantified as the number of nonsynonymous substitutions per nonsynonymous site.

Synonymous sites

Any sites within a gene at which some or all possible point mutations, depending on the degeneracy of the corresponding codon, do not change the encoded amino acid. Changes at synonymous sites are often presumed to be selectively neutral.

Linkage disequilibrium

A measure of whether alleles at two loci coexist in a population in a nonrandom fashion. Alleles that are in linkage disequilibrium are found together on the same haplotype more often than would be expected under free recombination.

McDonald–Kreitman test

A statistical test used to compare between-species divergence and within-species polymorphism at replacement and synonymous sites to infer selection acting on proteins.

Mutation accumulation lines

Unique genetic backgrounds created by multiple generations of controlled breeding in such a way as to minimize the action of natural selection and to maximize the retention of new mutations. They are used to identify spontaneous mutations and to study their phenotypic properties.

Stabilizing selection

A type of natural selection that favours intermediate phenotypes, such as when the population is close to its fitness optimum with respect to the trait.

Genetic draft

Stochastic fluctuations in allele frequencies in a population caused by repeated hard selective sweeps. Hypothesized to be the primary source of stochastic variation in allele frequencies in large populations, in which the sampling effects of genetic drift are relatively weak compared with smaller populations.

Genetic drift

Random fluctuations through time in the allele frequencies of a population caused by a sampling effect that is strongest in small populations. Drift can overwhelm the deterministic effects of natural selection if the selective differences between alleles are small.

Mutation-limited adaptation

When mutational input into a population is sufficiently low, the rate of adaptation will be limited by the input of new beneficial mutations. This common theoretical assumption will be violated in real species with populations that are large, subdivided or subject to frequent changes in selective regime.

Standing genetic variation

Allelic variation that is currently segregating within a population from old mutation events, as opposed to alleles that just arose by new mutation events.

Mutation–drift balance

The equilibrium between input of alleles into a population by mutation and their loss by genetic drift.

Population structure

The distribution of individuals into partially isolated, local subpopulations or demes that are interconnected by migration (gene flow).

Biased gene conversion

(BGC). Gene conversion is a non-reciprocal recombination process that causes one sequence to be overwritten with information from the other. BGC is when the two possible sequences act as donor templates with unequal probabilities.

Muller's ratchet

The irreversible accumulation of deleterious mutations in asexual populations of finite size. The average load of mutations increases over generations because the class of individuals that carry the smallest number of mutant alleles is occasionally lost by genetic drift. In the absence of recombination or compensatory mutation, this class can never be recreated. The process is named after H. J. Muller, who described it in 1964.

Selection coefficient

(s). A parameter describing the difference in average fitness between two genotypes when fitness is measured relative to the average fitness of one of the genotypes (known as the reference genotype).

Genetic architecture

The number, identity, phenotypic effects and population frequencies of the mutations that contribute to phenotypic variation.

Polygenic selection

Selection on a trait that has a genetic basis comprised of many gene loci (tens, hundreds or more). A given strength of selection on the phenotype will exert a weaker effect on any one locus when the trait is polygenic than when the trait is monogenic.

Purifying selection

Natural selection against deleterious alleles that arise in a population, preventing their increase in frequency.

Fitness-class coalescent

A version of structured coalescent models of evolution that traces how individuals descend by mutations through different fitness classes, rather than through time.

Transit time

The duration of time that elapses from when an allele first experiences selection to when it becomes fixed in a population.

F ST

A measure of population subdivision that indicates the proportion of genetic diversity found between populations relative to the amount within populations.

Population bottlenecks

Marked reductions in population size followed by the survival and expansion of a sample of the original population. It often results in the loss of genetic variation and a skewed site frequency spectrum.

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Cutter, A., Payseur, B. Genomic signatures of selection at linked sites: unifying the disparity among species. Nat Rev Genet 14, 262–274 (2013) doi:10.1038/nrg3425

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