Down the Penrose stairs, or how selection for fewer recombination hotspots maintains their existence

  1. Zachary Baker  Is a corresponding author
  2. Molly Przeworski
  3. Guy Sella
  1. Columbia University, United States

Abstract

In many species, meiotic recombination events tend to occur in narrow intervals of the genome, known as hotspots. In humans and mice, double strand break (DSB) hotspot locations are determined by the DNA-binding specificity of the zinc finger array of the PRDM9 protein, which is rapidly evolving at residues in contact with DNA. Previous models explained this rapid evolution in terms of the need to restore PRDM9 binding sites lost to gene conversion over time, under the assumption that more PRDM9 binding always leads to more DSBs. This assumption, however, does not align with current evidence. Recent experimental work indicates that PRDM9 binding on both homologs facilitates DSB repair, and that the absence of sufficient symmetric binding disrupts meiosis. We therefore consider an alternative hypothesis: that rapid PRDM9 evolution is driven by the need to restore symmetric binding because of its role in coupling DSB formation and efficient repair. To this end, we model the evolution of PRDM9 from first principles: from its binding dynamics to the population genetic processes that govern the evolution of the zinc finger array and its binding sites. We show that the loss of a small number of strong binding sites leads to the use of a greater number of weaker ones, resulting in a sharp reduction in symmetric binding and favoring new PRDM9 alleles that restore the use of a smaller set of strong binding sites. This decrease, in turn, drives rapid PRDM9 evolutionary turnover. Our results therefore suggest that the advantage of new PRDM9 alleles is in limiting the number of binding sites used effectively, rather than in increasing net PRDM9 binding. By extension, our model suggests that the evolutionary advantage of hotspots may have been to increase the efficiency of DSB repair and/or homolog pairing.

Data availability

All modeling code, as well as code used to generate the figures, is available at https://github.com/sellalab/PRDM9_model. Source Data files have been provided for Figures 2-6 and their associated figure supplements, as well as for Figures in appendices 4-5.

Article and author information

Author details

  1. Zachary Baker

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    zb267@cam.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1540-0731
  2. Molly Przeworski

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

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    Guy Sella, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5239-7930

Funding

National Institute of Health (R01 GM83098)

  • Molly Przeworski

National Institute of Health (R01 GM115889)

  • Guy Sella

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

Reviewing Editor

  1. Bernard de Massy, CNRS UM, France

Version history

  1. Preprint posted: September 28, 2022 (view preprint)
  2. Received: September 28, 2022
  3. Accepted: October 12, 2023
  4. Accepted Manuscript published: October 13, 2023 (version 1)

Copyright

© 2023, Baker 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

  • 291
    Page views
  • 86
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Zachary Baker
  2. Molly Przeworski
  3. Guy Sella
(2023)
Down the Penrose stairs, or how selection for fewer recombination hotspots maintains their existence
eLife 12:e83769.
https://doi.org/10.7554/eLife.83769

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Alex Mas Sandoval, Sara Mathieson, Matteo Fumagalli
    Research Article

    Cultural and socioeconomic differences stratify human societies and shape their genetic structure beyond the sole effect of geography. Despite mating being limited by sociocultural stratification, most demographic models in population genetics often assume random mating. Taking advantage of the correlation between sociocultural stratification and the proportion of genetic ancestry in admixed populations, we sought to infer the former process in the Americas. To this aim, we define a mating model where the individual proportions of the genome inherited from Native American, European and sub-Saharan African ancestral populations constrain the mating probabilities through ancestry-related assortative mating and sex bias parameters. We simulate a wide range of admixture scenarios under this model. Then, we train a deep neural network and retrieve good performance in predicting mating parameters from genomic data. Our results show how population stratification shaped by socially constructed racial and gender hierarchies have constrained the admixture processes in the Americas since the European colonisation and the subsequent Atlantic slave trade.

    1. Ecology
    2. Evolutionary Biology
    Hannah J Williams, Vivek H Sridhar ... Amanda D Melin
    Review Article

    Groups of animals inhabit vastly different sensory worlds, or umwelten, which shape fundamental aspects of their behaviour. Yet the sensory ecology of species is rarely incorporated into the emerging field of collective behaviour, which studies the movements, population-level behaviours, and emergent properties of animal groups. Here, we review the contributions of sensory ecology and collective behaviour to understanding how animals move and interact within the context of their social and physical environments. Our goal is to advance and bridge these two areas of inquiry and highlight the potential for their creative integration. To achieve this goal, we organise our review around the following themes: (1) identifying the promise of integrating collective behaviour and sensory ecology; (2) defining and exploring the concept of a ‘sensory collective’; (3) considering the potential for sensory collectives to shape the evolution of sensory systems; (4) exploring examples from diverse taxa to illustrate neural circuits involved in sensing and collective behaviour; and (5) suggesting the need for creative conceptual and methodological advances to quantify ‘sensescapes’. In the final section, (6) applications to biological conservation, we argue that these topics are timely, given the ongoing anthropogenic changes to sensory stimuli (e.g. via light, sound, and chemical pollution) which are anticipated to impact animal collectives and group-level behaviour and, in turn, ecosystem composition and function. Our synthesis seeks to provide a forward-looking perspective on how sensory ecologists and collective behaviourists can both learn from and inspire one another to advance our understanding of animal behaviour, ecology, adaptation, and evolution.