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Estimating the mutation load in human genomes

Key Points

  • Millions of new genetic variants have been discovered through sequencing studies and deposited in human genomic databases. Many of these, particularly rare variants, have been annotated as deleterious.

  • Recent research has examined whether different human populations have a varying burden of deleterious alleles — a concept referred to as mutation load.

  • Several recent studies have suggested that there is no significant difference among populations in the estimated number of deleterious alleles per individual. However, these analyses are sensitive to annotation prediction algorithms and summary statistics, leading to different, sometimes contradictory, interpretations.

  • These calculations also involved a number of simplifying assumptions, including additive allelic effects, no epistasis and simple distributions of selection coefficients across deleterious variants and across populations.

  • Following classical models of mutation load, we consider genotype frequencies in order to highlight how mutation load can change under different models of dominance.

  • Additionally, genetic drift has shifted the allele frequency spectrum of deleterious variants such that the genomes of individuals in Out-of-Africa populations carry more common deleterious variants.

  • The frequency distribution of deleterious variants has implications for characterizing the genetic architecture of diseases across populations.

Abstract

Next-generation sequencing technology has facilitated the discovery of millions of genetic variants in human genomes. A sizeable fraction of these variants are predicted to be deleterious. Here, we review the pattern of deleterious alleles as ascertained in genome sequencing data sets and ask whether human populations differ in their predicted burden of deleterious alleles — a phenomenon known as mutation load. We discuss three demographic models that are predicted to affect mutation load and relate these models to the evidence (or the lack thereof) for variation in the efficacy of purifying selection in diverse human genomes. We also emphasize why accurate estimation of mutation load depends on assumptions regarding the distribution of dominance and selection coefficients — quantities that remain poorly characterized for current genomic data sets.

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Figure 1: Proportion of deleterious variants found in an individual's genome classified by their frequency in the population (common versus rare).
Figure 2: Differences in the site frequency spectrum across populations for deleterious and neutral variants.
Figure 3: Schematic of different demographic models for the Out-of-Africa dispersal.
Figure 4: Mutation load under an additive and a recessive model.

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Acknowledgements

The authors thank K. Lohmueller, S. Peischl and L. Excoffier for discussion regarding these topics.

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Correspondence to Brenna M. Henn.

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FURTHER INFORMATION

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Supplementary information

Supplementary information S1 (box)

Variant Annotation Algorithms (PDF 171 kb)

Supplementary information S2 (figure)

Demographic history based on the site frequency spectrum and sharing of rare alleles. (PDF 249 kb)

Supplementary information S3 (figure)

Allele sharing versus allele frequency among European populations. (PDF 238 kb)

Glossary

Genetic load

Reduction in population fitness compared to a theoretical 'perfectly adapted' genotype. This reduction can be caused by the constant influx of new, deleterious mutations (the mutation load), but the genetic load also encompasses reduction in fitness caused by other phenomena, such as inbreeding and changing environment.

Neutral theory

A theory stating that the variation observed within and between species is largely determined by neutral mutation and genetic drift, and not by natural selection. Neutral theory became the basis for many additional population genetic models.

Substitution load

The difference between optimal fitness and mean fitness in a population undergoing a selective sweep. A locus undergoing a selective sweep will result in some individuals with lower fitness. If multiple loci are under adaptation, the number of individuals who will not reproduce in a generation becomes too large to realistically maintain a stable population. This substitution load puts a limit on the rate of adaptation and is sometimes referred to as Haldane's cost of selection.

Nearly neutral mutations

Variants of relatively weak selective effects that can be accounted for by an extension of neutral theory. Mutations that are slightly deleterious or slightly beneficial will behave as neutral depending on the relationship between population size and the selection coefficient. Because they can reach high frequency, nearly neutral variants can have a large impact on the genetic load, and their evolution is sensitive to fluctuations in population size.

Inbreeding load

Reduction in fitness caused by an excess of recessive homozygotes following inbreeding within a population. The inbreeding load measures the difference between the average fitness of individuals in a population and the fitness of a hypothetical randomly mating population with the same allele frequencies.

Mutation–selection balance

An equilibrium model in which the frequency of an allele is determined by recurrent mutation and the selection coefficient against the allele.

Consanguineous union

In clinical genetics, a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal to or higher than 0.0156.

Distribution of fitness effects

(DFE). The distribution of selection coefficients associated with newly arising mutations in a population.

Out-of-Africa

A model by which a small group of modern humans exited Africa approximately 50,000 years ago and dispersed into the Eurasian continents. This movement was accompanied by a severe, possibly tenfold, population bottleneck.

Serial founder effects

Serial expansion of a small ancestral population into a new geographical range; each new deme is created by sampling a small number of individuals to colonize the next location, resulting in a reduced effective population size.

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Henn, B., Botigué, L., Bustamante, C. et al. Estimating the mutation load in human genomes. Nat Rev Genet 16, 333–343 (2015). https://doi.org/10.1038/nrg3931

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