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PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2

View ORCID ProfileMaria Izabel A. Cavassim, View ORCID ProfileZachary Baker, View ORCID ProfileCarla Hoge, View ORCID ProfileMikkel H. Schierup, View ORCID ProfileMolly Schumer, View ORCID ProfileMolly Przeworski
doi: https://doi.org/10.1101/2021.06.08.447603
Maria Izabel A. Cavassim
1Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
2Department of Biological Sciences, Columbia University, New York City, United States
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  • ORCID record for Maria Izabel A. Cavassim
  • For correspondence: izabelcavassim@gmail.com zb267@cam.ac.uk
Zachary Baker
2Department of Biological Sciences, Columbia University, New York City, United States
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  • For correspondence: izabelcavassim@gmail.com zb267@cam.ac.uk
Carla Hoge
2Department of Biological Sciences, Columbia University, New York City, United States
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Mikkel H. Schierup
1Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
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Molly Schumer
4Department of Biology, Stanford University, Stanford, United States
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Molly Przeworski
2Department of Biological Sciences, Columbia University, New York City, United States
3Department of Systems Biology, Columbia University, New York City, United States
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Abstract

In most mammals and likely throughout vertebrates, the gene PRDM9 specifies the locations of meiotic double strand breaks; in mice and humans at least, it also aids in their repair. For both roles, many of the molecular partners remain unknown. Here, we take a phylogenetic approach to identify genes that may be interacting with PRDM9, by leveraging the fact that PRDM9 arose before the origin of vertebrates, but was lost many times, either partially or entirely––and with it, its role in recombination. As a first step, we characterize PRDM9 domain composition across 446 vertebrate species, inferring at least thirteen independent losses. We then use the interdigitation of PRDM9 orthologs across vertebrates to test whether it co-evolved with any of 241 candidate genes co-expressed with PRDM9 in mice or associated with recombination phenotypes in mammals. Accounting for the phylogenetic relationship among species, we find two genes whose presence and absence is unexpectedly coincident with that of PRDM9: ZCWPW1, which was recently shown to facilitate double strand break repair, and its paralog ZCWPW2, as well as more tentative evidence for TEX15 and FBXO47. ZCWPW2 is expected to be recruited to sites of PRDM9 binding; its tight coevolution with PRDM9 across vertebrates suggests that it is a key interactor, with a role either in recruiting the recombination machinery or in double strand break repair.

Author Summary Our understanding of meiotic recombination in mammals has seen great progress over the past 15 years, spurred in part by the convergence of lines of evidence from molecular biology, statistical genetics and evolutionary biology. We now know that in most mammals and likely in many vertebrates, the gene PRDM9 specifies the location of meiotic double strand breaks and that in mice and humans at least, it also aids in their repair. For both roles, however, many of the molecular partners remain unknown. To search for these, we take a phylogenetic approach, leveraging the fact that the complete PRDM9 has been lost at least thirteen times in vertebrates and thus that its presence is interdigitated across species. By this approach, we identify two genes whose presence or absence across vertebrates is coupled to the presence or absence of PRDM9, ZCWPW1 and ZCWPW2, as well as two genes for which the evidence is weaker, TEX15 and FBXO47. ZCWPW1 was recently shown to be recruited to sites of PRDM9 binding and to aid in the repair of double strand breaks. ZCWPW2 is likely recruited to sites of PRDM9 binding as well; its tight coevolution with PRDM9 across vertebrates suggests that it plays an important role either in double strand break formation, potentially as the missing link that recruits the recombination machinery to sites of PRDM9 binding, or in double strand break repair.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Joint first authors

  • 1- Figure 1 revised: from 379 species to 432 species 2- Anolis is found to have a complete ortholog of TEX15, and therefore, the co-evolutionary relationship between PRDM9 and TEX15 becomes more tentative. 3- Figure 2 revised in light of new PRDM9 losses. 4- Supplemental figures and files updated to support the new species.

  • https://www.dropbox.com/sh/pihq6a643fz21js/AAANGJWpALT42MCrrsJdlSUHa?dl=0

  • https://itol.embl.de/shared/izabelcavassim

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted July 29, 2021.
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PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2
Maria Izabel A. Cavassim, Zachary Baker, Carla Hoge, Mikkel H. Schierup, Molly Schumer, Molly Przeworski
bioRxiv 2021.06.08.447603; doi: https://doi.org/10.1101/2021.06.08.447603
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PRDM9 losses in vertebrates are coupled to those of paralogs ZCWPW1 and ZCWPW2
Maria Izabel A. Cavassim, Zachary Baker, Carla Hoge, Mikkel H. Schierup, Molly Schumer, Molly Przeworski
bioRxiv 2021.06.08.447603; doi: https://doi.org/10.1101/2021.06.08.447603

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