Mapping global and local coevolution across 600 species to identify novel homologous recombination repair genes
- Dana Sherill-Rofe1,11,
- Dolev Rahat1,2,11,
- Steven Findlay3,4,12,
- Anna Mellul1,12,
- Irene Guberman1,
- Maya Braun1,
- Idit Bloch1,
- Alon Lalezari1,
- Arash Samiei3,4,
- Ruslan Sadreyev5,6,7,
- Michal Goldberg8,
- Alexandre Orthwein3,4,9,10,
- Aviad Zick2 and
- Yuval Tabach1
- 1Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University of Jerusalem, Jerusalem 91120, Israel;
- 2Sharett Institute of Oncology, Hadassah Medical Center, Ein-Kerem, Jerusalem 91120, Israel;
- 3Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada;
- 4Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada;
- 5Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 6Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 7Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA;
- 8Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel;
- 9Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada;
- 10Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec H4A 3T2, Canada
Abstract
The homologous recombination repair (HRR) pathway repairs DNA double-strand breaks in an error-free manner. Mutations in HRR genes can result in increased mutation rate and genomic rearrangements, and are associated with numerous genetic disorders and cancer. Despite intensive research, the HRR pathway is not yet fully mapped. Phylogenetic profiling analysis, which detects functional linkage between genes using coevolution, is a powerful approach to identify factors in many pathways. Nevertheless, phylogenetic profiling has limited predictive power when analyzing pathways with complex evolutionary dynamics such as the HRR. To map novel HRR genes systematically, we developed clade phylogenetic profiling (CladePP). CladePP detects local coevolution across hundreds of genomes and points to the evolutionary scale (e.g., mammals, vertebrates, animals, plants) at which coevolution occurred. We found that multiscale coevolution analysis is significantly more biologically relevant and sensitive to detect gene function. By using CladePP, we identified dozens of unrecognized genes that coevolved with the HRR pathway, either globally across all eukaryotes or locally in different clades. We validated eight genes in functional biological assays to have a role in DNA repair at both the cellular and organismal levels. These genes are expected to play a role in the HRR pathway and might lead to a better understanding of missing heredity in HRR-associated cancers (e.g., heredity breast and ovarian cancer). Our platform presents an innovative approach to predict gene function, identify novel factors related to different diseases and pathways, and characterize gene evolution.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.241414.118.
- Received July 4, 2018.
- Accepted January 22, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
