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Reply to ‘Selective effects of heterozygous protein-truncating variants’

Nature Genetics volume 51, pages 3–4 (2019)Cite this article

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Cassa et al. reply — We kindly thank Brian Charlesworth and William Hill for their interest in our work and for raising an important question1. Our study estimated selection coefficients for heterozygous protein truncating variants (PTVs), shet, under the assumption of mutation-selection balance2. Although the mean number of rare deleterious PTVs per gene in a sample can be well approximated by the deterministic mutation-selection-balance expression, Charlesworth and Hill inquire whether it is fair to assume that the variance is unaltered by genetic drift. The deterministic scenario dictates that the variance is equal to the expectation; in other words, it assumes that the variance is dominated by the effects of sampling rather than by drift. Charlesworth and Hill present an analysis of the equilibrium model including drift, which suggests that variance might be substantially inflated for genes corresponding to the inferred mean heterozygous selection coefficient, \(\hat s_{{\mathrm{het}}} \approx 0.05\). They also question whether this inflation leads to a decrease in the variance of the overall distribution of heterozygous selection coefficients and whether the inclusion of drift might have affected our gene-specific estimates.

We investigated these issues with simulations that explicitly model genetic drift in the presence of a realistic demographic history and with purely data-driven approaches. Both the simulations and data suggest that the deterministic approximation is applicable for genes under strong selection, including genes with \(\hat s_{{\mathrm{het}}} = 0.05\), but drift affects selection estimates for the minority of human genes evolving under weak negative selection. The simulation-based estimates for strongly selected genes are similar to the deterministic estimates. Estimates of genes under weaker selection are monotonically increased. All analyses can be found in ref. 3 and are briefly described below.

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References

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Acknowledgements

We would like to thank J. Berg, G. Sella, M. Przeworski and A. Kondrashov for their helpful suggestions and feedback.

Author information

Author notes

  1. Donate Weghorn

    Present address: Centre for Genomic Regulation, Barcelona, Spain

  2. These authors contributed equally: Christopher A. Cassa, Donate Weghorn, Daniel J. Balick, Daniel M. Jordan.

Authors and Affiliations

  1. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Christopher A. Cassa, Donate Weghorn, Daniel J. Balick, David Nusinow & Shamil R. Sunyaev

  2. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Christopher A. Cassa, Donate Weghorn, Daniel J. Balick & Shamil R. Sunyaev

  3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    Christopher A. Cassa, Daniel G. MacArthur, Mark J. Daly & Shamil R. Sunyaev

  4. Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Daniel M. Jordan

  5. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Kaitlin E. Samocha, Anne O’Donnell-Luria, Daniel G. MacArthur & Mark J. Daly

  6. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA

    Kaitlin E. Samocha

  7. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Anne O’Donnell-Luria

  8. Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, WA, USA

    David R. Beier

  9. Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

    David R. Beier

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  1. Christopher A. Cassa
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Correspondence to David R. Beier or Shamil R. Sunyaev.

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Cassa, C.A., Weghorn, D., Balick, D.J. et al. Reply to ‘Selective effects of heterozygous protein-truncating variants’. Nat Genet 51, 3–4 (2019). https://doi.org/10.1038/s41588-018-0301-y

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