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

Abstract
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Abstract

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

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https://cglgenomics.ucsc.edu/data/cactus/
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github.

https://github.com/quinlan-lab/ceph-dnm-manuscript
1. Lindsay et al
(2019) Mouse de novo mutations
Supplementary Data 1.

https://www.nature.com/articles/s41467-019-12023-w#Sec41

Article and author information

Author details

Marc de Manuel

Department of Biological Sciences, Columbia University, New York, United States

For correspondence
md3914@columbia.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-1245-0127
Felix L Wu

Department of Biological Sciences, Columbia University, New York, United States

For correspondence
flw2113@cumc.columbia.edu

Competing interests
No competing interests declared.
Molly Przeworski

Department of Systems Biology, Columbia University, New York, United States

For correspondence
mp3284@columbia.edu

Competing interests
Molly Przeworski, Senior editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-5369-9009

Funding

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.

Copyright

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.