A compendium of human gene functions derived from evolutionary modelling
Authors: Feuermann Marc , Mi Huaiyu , Gaudet Pascale , Muruganujan Anushya , Lewis Suzanna E. , Ebert Dustin , Mushayahama Tremayne ,   Gene Ontology Consortium, Aleksander Suzanne A. , Balhoff James , Carbon Seth , Cherry J. Michael , Drabkin Harold J. , Harris Nomi L. , Hill David P. , Lee Raymond , Logie Colin , Moxon Sierra , Mungall Christopher J. , Sternberg Paul W. , Van Auken Kimberly ,   CACAO/EcoliWiki, Ramsey Jolene , Siegele Deborah A. ,   dictyBase, Chisholm Rex L. , Fey Petra ,   Evidence and Conclusion Ontology, Giglio Michelle , Nadendla Suvarna ,   FlyBase, Antonazzo Giulia , Attrill Helen , Brown Nicholas H. , Garapati Phani V. , Marygold Steven ,   Functional Gene Annotation UCL, Ahmed Saadullah H. , Asanitthong Praoparn , Buitrago Diana Luna , Erdol Meltem N. , Gage Matthew C. , Huang Siyao , Kadhum Mohamed Ali , Li Kan Yan Chloe , Long Miao , Michalak Aleksandra , Pesala Angeline , Pritazahra Armalya , Saverimuttu Shirin C. C. , Su Renzhi , Xu Qianhan , Lovering Ruth C. ,   Mouse Genome Informatics, Blake Judith , Christie Karen , Corbani Lori , Dolan Mary E. , Ni Li , Sitnikov Dmitry , Smith Cynthia ,   PomBase, Lera-Ramirez Manuel , Rutherford Kim , Wood Valerie ,   Reactome, D’Eustachio Peter ,   Rat Genome Database, Demos Wendy M. , De Pons Jeffrey L. , Dwinell Melinda R. , Hayman G. Thomas , Kaldunski Mary L. , Kwitek Anne E. , Laulederkind Stanley J. F. , Smith Jennifer R. , Tutaj Marek A. , Vedi Mahima , Wang Shur-Jen ,   Saccharomyces Genome Database, Engel Stacia R. , Karra Kalpana , Miyasato Stuart R. , Nash Robert S. , Skrzypek Marek S. , Weng Shuai , Wong Edith D. ,   SynGO Consortium, Achsel Tilmann , Andres-Alonso Maria , Bagni Claudia , Bayés Àlex , Biederer Thomas , Brose Nils , Chua John Jia En , Coba Marcelo P. , Cornelisse L. Niels , de Juan-Sanz Jaime , Goldschmidt Hana L. , Gundelfinger Eckart D. , Huganir Richard L. , Imig Cordelia , Jahn Reinhard , Jung Hwajin , Kaeser Pascal S. , Kim Eunjoon , Koopmans Frank , Kreutz Michael R. , Lipstein Noa , MacGillavry Harold D. , McPherson Peter S. , O’Connor Vincent , Pielot Rainer , Ryan Timothy A. , Sala Carlo , Sheng Morgan , Smalla Karl-Heinz , Smit A. B. , Toonen Ruud F. , van Weering Jan R. T. , Verhage Matthijs , Verpelli Chiara ,   The Arabidopsis Information Resource (TAIR), Bakker Erika , Berardini Tanya Z. , Reiser Leonore ,   UniProt Consortium (Swiss-Prot Group), Auchincloss Andrea , Axelsen Kristian , Argoud-Puy Ghislaine , Blatter Marie-Claude , Boutet Emmanuel , Breuza Lionel , Bridge Alan , Casals-Casas Cristina , Coudert Elisabeth , Estreicher Anne , Famiglietti Maria Livia , Gos Arnaud , Gruaz-Gumowski Nadine , Hulo Chantal , Hyka-Nouspikel Nevila , Jungo Florence , Le Mercier Philippe , Lieberherr Damien , Masson Patrick , Morgat Anne , Pedruzzi Ivo , Pourcel Lucille , Poux Sylvain , Rivoire Catherine , Sundaram Shyamala ,   UniProt Consortium (EMBL-EBI), Bowler-Barnett Emily , Bye-A-Jee Hema , Denny Paul , Ignatchenko Alexandr , Ishtiaq Rizwan , Lock Antonia , Lussi Yvonne , Magrane Michele , Martin Maria J. , Orchard Sandra , Raposo Pedro , Speretta Elena , Tyagi Nidhi , Warner Kate , Zaru Rossana ,   WormBase, Chan Juancarlos , Diamantakis Stavros , Raciti Daniela ,   Xenbase, Fisher Malcolm , James-Zorn Christina , Ponferrada Virgilio , Zorn Aaron ,   Zebrafish Information Network (ZFIN), Ramachandran Sridhar , Ruzicka Leyla , Westerfield Monte , Thomas Paul D. 
Published: February 2025

Abstract
A comprehensive, computable representation of the functional repertoire of all macromolecules encoded within the human genome is a foundational resource for biology and biomedical research. The Gene Ontology Consortium has been working towards this goal by generating a structured body of information about gene functions, which now includes experimental findings reported in more than 175,000 publications for human genes and genes in experimentally tractable model organisms1,2. Here, we describe the results of a large, international effort to integrate all of these findings to create a representation of human gene functions that is as complete and accurate as possible. Specifically, we apply an expert-curated, explicit evolutionary modelling approach to all human protein-coding genes. This approach integrates available experimental information across families of related genes into models that reconstruct the gain and loss of functional characteristics over evolutionary time. The models and the resulting set of 68,667 integrated gene functions cover approximately 82% of human protein-coding genes. The functional repertoire reveals a marked preponderance of molecular regulatory functions, and the models provide insights into the evolutionary origins of human gene functions. We show that our set of descriptions of functions can improve the widely used genomic technique of Gene Ontology enrichment analysis. The experimental evidence for each functional characteristic is recorded, thereby enabling the scientific community to help review and improve the resource, which we have made publicly available.