The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development

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Abstract

Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination.

Data availability

All code has been posted on Github https://github.com/MarcoColnaghi1990/colnaghi-pomiankowski-lane-elife-2021

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Marco Colnaghi

Genetics, Evolution and Environment, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5641-9324
Andrew Pomiankowski

Genetics, Evolution and Environment, University College London, London, United Kingdom

For correspondence
a.pomiankowski@ucl.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5171-8755
Nick Lane

Genetics, Evolution and Environment, UCL Faculty of Life Sciences, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5433-3973

Funding

Engineering and Physical Sciences Research Council (EP/F500351/1)

Andrew Pomiankowski

Engineering and Physical Sciences Research Council (EP/I017909/1)

Andrew Pomiankowski

Natural Environment Research Council (NE/R010579/1)

Andrew Pomiankowski

Biotechnology and Biological Sciences Research Council (BB/S003681/1)

Nick Lane

bgc3 (.none.)

Nick Lane

Biotechnology and Biological Sciences Research Council (BB/V003542/1)

Marco Colnaghi
Andrew Pomiankowski
Nick Lane

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.