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Cited by 281Evolution and Genetic DynamicsGenomics and Rare DiseasesGenetic Associations and Epidemiology

Estimating the mutation load in human genomes

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Henn, Brenna M., Botigué, Laura R., Bustamante, Carlos D., Clark, Andrew G., Gravel, Simon·2015·Nature Reviews Genetics
DOI 10.1038/nrg3931PMC PMC4959039
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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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  • Differences in environmental exposure, gene-gene interactions, gene-environment interactions, historical population size dynamics, statistical noise, some potential causal effect differences, and/or other factors will further limit generalizability for genetic risk scores in an unpredictable, trait-specific fashion.

    “Differences in environmental exposure, gene-gene interactions, gene-environment interactions, historical population size dynamics, statistical noise, some potential causal effect differences, and/or other factors will further limit generalizability for genetic risk scores in an unpredictable, trait-specific fashion46–49.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [47]

    The Conclusions (page unavailable) discuss epistasis, adaptation to different environments, and differences in complex-disease architecture across populations. Demographic Simulations of Mutation Load (page unavailable) discusses bottlenecks and founder effects. The paper does not establish that these factors limit genetic risk-score generalizability in an unpredictable, trait-specific way, and the cited passages do not address statistical noise or gene–environment interactions as risk-score limitations. (LLM, conf=0.82)

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  • A related computation of the overall influence of natural selection in human history, relying on measures of selection against deleterious variants rather than directional selection of favorable variants, does not suggest strong systematic differences in the magnitude of selection among different continental population groups.

    “However, a related computation of the overall influence of natural selection in human history, relying on measures of selection against deleterious variants rather than directional selection of favorable variants, does not suggest strong systematic differences in the magnitude of selection among different continental population groups [50–52]”

    From Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences (2019) · cites this paper as [52]

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  • Some researchers have argued for a greater level of deleterious variation in non-Africans rather than in Africans, a pattern opposite to what might be expected given the direction of health disparities.

    “indeed, some researchers have argued for a greater level of deleterious variation in non-Africans rather than in Africans [50, 52], a pattern opposite to what might be expected given the direction of health disparities.”

    From Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences (2019) · cites this paper as [52]

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Cited by

Sorted by citations

Authors
Henn, B. M., Botigué, L. R., Bustamante, C. D., Clark, A. G., & Gravel, S.
Affiliations
  • Stony Brook University (US)
  • Stanford Medicine (US)
  • Cornell University (US)
  • McGill University and Génome Québec Innovation Centre (CA)
Corresponding author
Henn, Brenna M.
ORCID
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2015-05-12
Volume
16
Issue
6
Pages
333-343
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/nrg3931
PMC
PMC4959039
OpenAlex
W1573669151
Cited by
281
References
11
Citations by year
2026: 8 · 2025: 16 · 2024: 19 · 2023: 32 · 2022: 27 · 2021: 22 · 2020: 26 · 2019: 20 · 2018: 35 · 2017: 27 · 2016: 39 · 2015: 10
FWCI
4.69
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Human Genome Research Institute (R01HG003229)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
mutational burden, deleterious alleles, human genome, purifying selection, selection coefficients, dominance coefficient, population variation, demographic models, genetic variants
MeSH terms
Gene Frequency, Genes, Dominant, Humans, Models, Genetic, Mutation, Selection, Genetic, Genome, Human, Founder Effect, Genetic Drift, Human Migration

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