Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates

  1. Zachary Baker  Is a corresponding author
  2. Molly Schumer
  3. Yuki Haba
  4. Lisa Bashkirova
  5. Chris Holland
  6. Gil G Rosenthal
  7. Molly Przeworski  Is a corresponding author
  1. Columbia University, United States
  2. Centro de Investigaciones Científicas de las Huastecas "Aguazarca", Mexico

Abstract

Studies of highly diverged species have revealed two mechanisms by which meiotic recombination is directed to the genome—through PRDM9 binding or by targeting promoter-like features—that lead to dramatically different evolutionary dynamics of hotspots. Here, we identify PRDM9 orthologs from genome and transcriptome data in 225 species. We find the complete PRDM9 ortholog across distantly related vertebrates but, despite this broad conservation, infer a minimum of six partial and three complete losses. Strikingly, taxa carrying the complete ortholog of PRDM9 are precisely those with rapid evolution of its predicted binding affinity, suggesting that all domains are necessary for directing recombination. Indeed, as we show, swordtail fish carrying only a partial but conserved ortholog share recombination properties with PRDM9 knock-outs.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zachary Baker

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    ztb2002@columbia.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1540-0731
  2. Molly Schumer

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  3. Yuki Haba

    Department of Evolution, Ecology and Environmental Biology, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  4. Lisa Bashkirova

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  5. Chris Holland

    Centro de Investigaciones Científicas de las Huastecas "Aguazarca", Hidalgo, Mexico
    Competing interests
    No competing interests declared.
  6. Gil G Rosenthal

    Centro de Investigaciones Científicas de las Huastecas "Aguazarca", Hidalgo, Mexico
    Competing interests
    No competing interests declared.
  7. Molly Przeworski

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    mp3284@columbia.edu
    Competing interests
    Molly Przeworski, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5369-9009

Funding

National Institutes of Health (R01 GM83098)

  • Molly Przeworski

National Science Foundation (DDIG DEB-1405232)

  • Molly Schumer

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, Institute of Human Genetics, CNRS UPR 1142, France

Ethics

Animal experimentation: Animals used for this study were handled according to the approved institutional animal care and use committee (IACUC) protocol AUP# - IACUC 2013-0168 of Texas A&M University. All individuals used for dissections were first treated with MS-222 for anesthesia to minimize suffering before being euthanized.

Version history

  1. Received: December 10, 2016
  2. Accepted: June 3, 2017
  3. Accepted Manuscript published: June 6, 2017 (version 1)
  4. Version of Record published: July 20, 2017 (version 2)

Copyright

© 2017, 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

  • 4,973
    views
  • 676
    downloads
  • 113
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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 Schumer
  3. Yuki Haba
  4. Lisa Bashkirova
  5. Chris Holland
  6. Gil G Rosenthal
  7. Molly Przeworski
(2017)
Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates
eLife 6:e24133.
https://doi.org/10.7554/eLife.24133

Share this article

https://doi.org/10.7554/eLife.24133

Further reading

    1. Genetics and Genomics
    Julie Clément, Bernard de Massy
    Insight

    The ways in which recombination sites are determined during meiosis are becoming clearer following a phylogenomic analysis for 225 different species.

    1. Genetics and Genomics
    2. Neuroscience
    Bohan Zhu, Richard I Ainsworth ... Javier González-Maeso
    Research Article

    Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.