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

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.

Scalable Phylogenetic Profiling using MinHash Uncovers Likely Eukaryotic Sexual Reproduction Genes

“…When they were first implemented, profiles were constructed as binary vectors of presence and absence across species [3] . Since then, variants have been proposed, which take continuous values [9] -such as alignment scores with the gene of a reference species [11] -or which count the number of paralogs present in each species. Yet other variants convey the number of events on branches of the species tree [6] .…”

“…Multiple successful applications of phylogenetic profiling in eukaryotes have been published in recent years, e.g. to infer small RNA pathway genes [8] , the kinetochore network [9] , ciliary genes [10] , or homologous recombination repair genes [11] .…”

Scalable phylogenetic profiling using MinHash uncovers likely eukaryotic sexual reproduction genes

“…Multiple successful applications of phylogenetic profiling in eukaryotes have been published in recent years. For example, they have been used to infer small RNA pathway genes [9], the kinetochore network [10], ciliary genes [11], or homologous recombination repair genes [12].…”

Conservation motifs - a novel evolutionary-based classification of proteins

“…The protein phylogenetic profiling data was generated as previously described 13,14,21 . 1154 proteomes were downloaded from both NCBI's RefSeq non-redundant protein database and Uniprot.…”

“…Over the past decade, NPP has been used to discover genetic interactions and novel genes in the RNA interference pathway, RNA methylation, and various human diseases including cancer [13][14][15][16][17][18][19][20] . Recently we demonstrated the importance of focusing on different taxonomic clades as it can improve the ability to identify novel factors in different pathways, specifically in the homologous recombination repair pathway 21 .…”