A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell divisions

  1. Marc de Manuel  Is a corresponding author
  2. Felix L Wu  Is a corresponding author
  3. Molly Przeworski  Is a corresponding author
  1. Columbia University, United States


In humans and other mammals, germline mutations are more likely to arise in fathers than in mothers. Although this sex bias has long been attributed to DNA replication errors in spermatogenesis, recent evidence from humans points to the importance of mutagenic processes that do not depend on cell division, calling into question our understanding of this basic phenomenon. Here, we infer the ratio of paternal-to-maternal mutations, α, in 42 species of amniotes, from putatively neutral substitution rates of sex chromosomes and autosomes. Despite marked differences in gametogenesis, physiologies and environments across species, fathers consistently contribute more mutations than mothers in all the species examined, including mammals, birds and reptiles. In mammals, α is as high as 4 and correlates with generation times; in birds and snakes, α appears more stable around 2. These observations are consistent with a simple model, in which mutations accrue at equal rates in both sexes during early development and at a higher rate in the male germline after sexual differentiation, with a conserved paternal-to-maternal ratio across species. Thus, α may reflect the relative contributions of two or more developmental phases to total germline mutations, and is expected to depend on generation time even if mutations do not track cell divisions.

Data availability

All source data and scripts to reproduce the findings in the manuscript can be found at https://github.com/flw88/mut_sex_bias_amniotes

The following previously published data sets were used

Article and author information

Author details

  1. Marc de Manuel

    Department of Biological Sciences, Columbia University, New York, United States
    For correspondence
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1245-0127
  2. Felix L Wu

    Department of Biological Sciences, Columbia University, New York, United States
    For correspondence
    Competing interests
    No competing interests declared.
  3. Molly Przeworski

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    Competing interests
    Molly Przeworski, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5369-9009


National Institutes of Health (GM122975)

  • Molly Przeworski

Human Frontier Science Program (LT000257/2021-L)

  • Marc de Manuel

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

Reviewing Editor

  1. Yukiko M Yamashita, Whitehead Institute/MIT, United States

Publication history

  1. Received: May 5, 2022
  2. Accepted: August 1, 2022
  3. Accepted Manuscript published: August 2, 2022 (version 1)


© 2022, de Manuel 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.


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  1. Marc de Manuel
  2. Felix L Wu
  3. Molly Przeworski
A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell divisions
eLife 11:e80008.

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