Background selection and biased gene conversion affect more than 95% of the human genome and bias demographic inferences

Abstract

Disentangling the effect on genomic diversity of natural selection from that of demography is notoriously difficult, but necessary to properly reconstruct the history of species. Here, we use high-quality human genomic data to show that purifying selection at linked sites (i.e. background selection, BGS) and GC-biased gene conversion (gBGC) together affect as much as 95% of the variants of our genome. We find that the magnitude and relative importance of BGS and gBGC are largely determined by variation in recombination rate and base composition. Importantly, synonymous sites and non-transcribed regions are also affected, albeit to different degrees. Their use for demographic inference can lead to strong biases. However, by conditioning on genomic regions with recombination rates above 1.5 cM/Mb and mutation types (C↔G, A↔T), we identify a set of SNPs that is mostly unaffected by BGS or gBGC, and that avoids these biases in the reconstruction of human history.

Data availability

All data generated and script to analyse them is provided on the dryad repesitory: http://datadryad.org/review?doi=doi:10.5061/dryad.t76fk80

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Fanny Pouyet

    Institute of Ecology and Evolution, University of Bern, Berne, Switzerland
    For correspondence
    fanny.pouyet@iee.unibe.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5614-6998
  2. Simon Aeschbacher

    Institute of Ecology and Evolution, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexandre Thiéry

    Institute of Ecology and Evolution, University of Bern, Bern, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Laurent Excoffier

    Institute of Ecology and Evolution, University of Bern, Bern, Switzerland
    For correspondence
    laurent.excoffier@iee.unibe.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7507-6494

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B-166605)

  • Laurent Excoffier

University of Berkeley (Visiting Miller Professorship)

  • Laurent Excoffier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2018, Pouyet et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,616
    views
  • 1,035
    downloads
  • 127
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Fanny Pouyet
  2. Simon Aeschbacher
  3. Alexandre Thiéry
  4. Laurent Excoffier
(2018)
Background selection and biased gene conversion affect more than 95% of the human genome and bias demographic inferences
eLife 7:e36317.
https://doi.org/10.7554/eLife.36317

Share this article

https://doi.org/10.7554/eLife.36317

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Steven Henikoff, David L Levens
    Insight

    A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease
    Nicole Herrmann May, Anh Cao ... Tom Beneke
    Research Advance

    The ability to analyze the function of all genes in a genome is highly desirable, yet challenging in Leishmania due to a repetitive genome, limited DNA repair mechanisms, and lack of RNA interference in most species. While our introduction of a cytosine base editor (CBE) demonstrated potential to overcome these limitations (Engstler and Beneke, 2023), challenges remained, including low transfection efficiency, variable editing rates across species, parasite growth effects, and competition between deleterious and non-deleterious mutations. Here, we present an optimized approach addressing these issues. We identified a T7 RNAP promoter variant ensuring high editing rates across Leishmania species without compromising growth. A revised CBE single-guide RNAs (sgRNAs) scoring system was developed to prioritize STOP codon generation. Additionally, a triple-expression construct was created for stable integration of CBE sgRNA expression cassettes into a Leishmania safe harbor locus using AsCas12a ultra-mediated DNA double-strand breaks, increasing transfection efficiency by ~400-fold to 1 transfectant per 70 transfected cells. Using this improved system for a small-scale proof-of-principle pooled screen, we successfully confirmed the essential and fitness-associated functions of CK1.2, CRK2, CRK3, AUK1/AIRK, TOR1, IFT88, IFT139, IFT140, and RAB5A in Leishmania mexicana, demonstrating a significant improvement over our previous method. Lastly, we show the utility of co-expressing AsCas12a ultra, T7 RNAP, and CBE for hybrid CRISPR gene replacement and base editing within the same cell line. Overall, these improvements will broaden the range of possible gene editing applications in Leishmania species and will enable a variety of loss-of-function screens in the near future.