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Accurate determination of the evolutionary relationships between genes is a foundational challenge in biology. Homology-evolutionary relatedness-is in many cases readily determined based on sequence similarity analysis. By contrast, whether or not two genes directly descended from a common ancestor by a speciation event (orthologs) or duplication event (paralogs) is more challenging, yet provides critical information on the history of a gene. Since 2009, this task has been the focus of the Quest for Orthologs (QFO) Consortium. The sixth QFO meeting took place in Okazaki, Japan in conjunction with the 67th National Institute for Basic Biology conference. Here, we report recent advances, applications, and oncoming challenges that were discussed during the conference. Steady progress has been made toward standardization and scalability of new and existing tools. A feature of the conference was the presentation of a panel of accessible tools for phylogenetic profiling and several developments to bring orthology beyond the gene unit-from domains to networks. This meeting brought into light several challenges to come: leveraging orthology computations to get the most of the incoming avalanche of genomic data, integrating orthology from domain to biological network levels, building better gene models, and adapting orthology approaches to the broad evolutionary and genomic diversity recognized in different forms of life and viruses.

Accurate determination of the evolutionary relationships between genes is a foundational challenge in biology. Homology—evolutionary relatedness—is in many cases readily determined based on sequence similarity analysis. By contrast, whether or not two genes directly descended from a common ancestor by a speciation event (orthologs) or duplication event (paralogs) is more challenging, yet provides critical information on the history of a gene. Since 2009, this task has been the focus of the Quest for Orthologs (QFO) Consortium. The sixth QFO meeting took place in Okazaki, Japan in conjunction with the 67th National Institute for Basic Biology conference. Here, we report recent advances, applications, and oncoming challenges that were discussed during the conference. Steady progress has been made toward standardization and scalability of new and existing tools. A feature of the conference was the presentation of a panel of accessible tools for phylogenetic profiling and several developments to bring orthology beyond the gene unit—from domains to networks. This meeting brought into light several challenges to come: leveraging orthology computations to get the most of the incoming avalanche of genomic data, integrating orthology from domain to biological network levels, building better gene models, and adapting orthology approaches to the broad evolutionary and genomic diversity recognized in different forms of life and viruses., We thank the National Institute for Basic Biology, the Japanese Society for Bioinformatics and the Daiko Foundation for supporting the 67th NIBB Conference/The 6th Quest for Orthologs Meeting. We wish to acknowledge the following support for attending the meetings and/or writing this manuscript: EMBO Young Investigator meeting grant (to C.D.). Service and Infrastructure grant from the Swiss Institute of Bioinformatics, Swiss National Science Foundation [183723] (to C.D.); IdEX Unistra in the framework of the Investments for the future program of the French government (to O.L. and Y.N.); NSF (Award No. 1724300), KAKENHI (Grant No. JP18H01325) (to S.E.M.); support by the research funding program Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz (LOEWE) of the State of Hessen, Research Center for Translational Biodiversity Genomics (TBG) (to I.E.); funding from the Wellcome Trust (108749/Z/15/Z) and the European Molecular Biology Laboratory (to M.P.); National Human Genome Research Institute, National Institutes of Health NIH (grant no. U41HG002273), National Science Foundation NSF (award no. 1917302) (to P.D.T.); Japan Society for the Promotion of Science (16H06279 and 19F19089) (to W.I. and S.C.)., Peer Reviewed, "Article signat per 14 autors/es: Benjamin Linard, Ingo Ebersberger, Shawn E McGlynn, Natasha Glover, Tomohiro Mochizuki, Mateus Patricio, Odile Lecompte, Yannis Nevers, Paul D Thomas, Toni Gabaldón, Erik Sonnhammer, Christophe Dessimoz, Ikuo Uchiyama, QFO Consortium" "Members of the Quest for Orthologs (QFO) Consortium: Adrian Altenhoff, Aida Ouangraoua, Alex Warwick Vesztrocy, Benjamin Linard, Christophe Dessimoz, Damian Szklarczyk, Dannie Durand, David Emms, David Moi, David Thybert, Erik Sonnhammer, Evgenia Kriventseva, Haiming Tang, Hirokazu Chiba, Ikuo Uchiyama, Ingo Ebersberger, Jaime Huerta-Cepas, Jesualdo Tomas Fernandez-Breis, Judith A. Blake, Leszek Pryszcz, Maria-Jesus Martin, Marina Marcet Houben, Mateus Patricio, Matthieu Muffato, Natasha Glover, Odile Lecompte, Paul D. Thomas, Philipp Schiffer, Salvador Capella-Gutierrez, Salvatore Cosentino, Shawn E McGlynn, Shigehiro Kuraku, Sofia Forslund, Steven Kelly, Suzanna Lewis, Tamsin Jones, Tarcisio Mendes de Farias, Taro Maeda, Toni Gabaldon, Wataru Iwasaki, William Pearson, Yan Wang, Yannis Nevers, Yuichiro Hara. All members acknowledged and gave their approval to the content of this manuscript.", Postprint (published version)