Systematic Discovery of Human Gene Function and Principles of Modular Organization through Phylogenetic Profiling

Gautam Dey, Ariel Jaimovich, Sean Collins, Akiko Seki, Tobias Meyer

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Functional links between genes can be predicted using phylogenetic profiling, by correlating the appearance and loss of homologs in subsets of species. However, effective genome-wide phylogenetic profiling has been hindered by the large fraction of human genes related to each other through historical duplication events. Here, we overcame this challenge by automatically profiling over 30,000 groups of homologous human genes (orthogroups) representing the entire protein-coding genome across 177 eukaryotic species (hOP profiles). By generating a full pairwise orthogroup phylogenetic co-occurrence matrix, we derive unbiased genome-wide predictions of functional modules (hOP modules). Our approach predicts functions for hundreds of poorly characterized genes. The results suggest evolutionary constraints that lead components of protein complexes and metabolic pathways to co-evolve while genes in signaling and transcriptional networks do not. As a proof of principle, we validated two subsets of candidates experimentally for their predicted link to the actin-nucleating WASH complex and cilia/basal body function.

Original languageEnglish (US)
Pages (from-to)993-1006
Number of pages14
JournalCell Reports
Volume10
Issue number6
DOIs
StatePublished - Feb 17 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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