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Genome Res. 2019 Mar;29(3):439-448. doi: 10.1101/gr.241414.118. Epub 2019 Feb 4.

Mapping global and local coevolution across 600 species to identify novel homologous recombination repair genes.

Author information

1
Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
2
Sharett Institute of Oncology, Hadassah Medical Center, Ein-Kerem, Jerusalem 91120, Israel.
3
Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
4
Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
5
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
6
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
7
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
8
Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
9
Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.
10
Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec H4A 3T2, Canada.
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Contributed equally

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.

PMID:
30718334
PMCID:
PMC6396423
DOI:
10.1101/gr.241414.118
[Indexed for MEDLINE]
Free PMC Article

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