A roadmap for the functional annotation of protein families: a community perspective

Valérie de Crécy-Lagard¹, Rocio Amorin de Hegedus², Cecilia Arighi³, Jill Babor¹, Alex Bateman⁴, Ian Blaby⁵, Crysten Blaby-Haas⁶, Alan J Bridge⁷, Stephen K Burley⁸, Stacey Cleveland¹, Lucy J Colwell⁹, Ana Conesa¹⁰, Christian Dallago¹¹, Antoine Danchin¹², Anita de Waard¹³, Adam Deutschbauer¹⁴, Raquel Dias¹, Yousong Ding¹⁵, Gang Fang¹⁶, Iddo Friedberg¹⁷, John Gerlt¹⁸, Joshua Goldford¹⁹, Mark Gorelik¹, Benjamin M Gyori²⁰, Christopher Henry²¹, Geoffrey Hutinet¹, Marshall Jaroch¹, Peter D Karp²², Liudmyla Kondratova², Zhiyong Lu²³, Aron Marchler-Bauer²³, Maria-Jesus Martin⁴, Claire McWhite²⁴, Gaurav D Moghe²⁵, Paul Monaghan²⁶, Anne Morgat⁷, Christopher J Mungall¹⁴, Darren A Natale²⁷, William C Nelson²⁸, Seán O'Donoghue²⁹, Christine Orengo³⁰, Katherine H O'Toole³¹, Predrag Radivojac³², Colbie Reed¹, Richard J Roberts³¹, Dmitri Rodionov³³, Irina A Rodionova³⁴, Jeffrey D Rudolf³⁵, Lana Saleh³¹, Gloria Sheynkman³⁶, Francoise Thibaud-Nissen²³, Paul D Thomas³⁷, Peter Uetz³⁸, David Vallenet³⁹, Erica Watson Carter⁴⁰, Peter R Weigele³¹, Valerie Wood⁴¹, Elisha M Wood-Charlson¹⁴, Jin Xu⁴⁰

Affiliations

¹ Department of Microbiology and Cell Sciences, University of Florida, Gainesville, FL 32611, USA.
² Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
³ Department of Computer and Information Sciences, University of Delaware, Newark, DE 19713, USA.
⁴ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, UK.
⁵ US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁶ Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
⁷ Swiss-Prot group, SIB Swiss Institute of Bioinformatics, Centre Medical Universitaire, Geneva 4 CH-1211, Switzerland.
⁸ RCSB Protein Data Bank, Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
⁹ Departmenf of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
¹⁰ Spanish National Research Council, Institute for Integrative Systems Biology, Paterna, Valencia 46980, Spain.
¹¹ TUM (Technical University of Munich) Department of Informatics, Bioinformatics & Computational Biology, i12, Boltzmannstr. 3, Garching/Munich 85748, Germany.
¹² School of Biomedical Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, SAR Hong Kong 999077, China.
¹³ Research Collaboration Unit, Elsevier, Jericho, VT 05465, USA.
¹⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
¹⁵ Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL 32610, USA.
¹⁶ NYU-Shanghai, Shanghai 200120, China.
¹⁷ Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA.
¹⁸ Institute for Genomic Biology and Departments of Biochemistry and Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
¹⁹ Physics of Living Systems, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
²⁰ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
²¹ Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL 60439, USA.
²² Bioinformatics Research Group, SRI International, Menlo Park, CA 94025, USA.
²³ National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), National Institutes of Health (NIH), 8600 Rockville Pike, Bethesda, MD 20817, USA.
²⁴ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA.
²⁵ Plant Biology Section, School of Integrative Plant Science, Cornell University, Ithaca, NY 14853, USA.
²⁶ Department of Agricultural Education and Communication, University of Florida, Gainesville, FL 32611, USA.
²⁷ Georgetown University Medical Center, Washington, DC 20007, USA.
²⁸ Biological Sciences Division, Pacific Northwest National Laboratories, Richland, WA 99354, USA.
²⁹ School of Biotechnology and Biomolecular Sciences, University of NSW, Sydney, NSW 2052, Australia.
³⁰ Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
³¹ New England Biolabs, Ipswich, MA 01938, USA.
³² Khoury College of Computer Sciences, Northeastern University, Boston, MA 02115, USA.
³³ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
³⁴ Department of Bioengineering, Division of Engineering, University of California at San Diego, La Jolla, CA 92093-0412, USA.
³⁵ Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
³⁶ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
³⁷ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA 90033, USA.
³⁸ Center for Biological Data Science, Virginia Commonwealth University, Richmond, VA 23284, USA.
³⁹ LABGeM, Génomique Métabolique, CEA, Genoscope, Institut François Jacob, Université d'Évry, Université Paris-Saclay, CNRS, Evry 91057, France.
⁴⁰ Department of Plant Pathology, University of Florida Citrus Research and Education Center, 700 Experiment Station Rd., Lake Alfred, FL 33850, USA.
⁴¹ Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.

PMID: 35961013
PMCID: PMC9374478
DOI: 10.1093/database/baac062

A roadmap for the functional annotation of protein families: a community perspective

Valérie de Crécy-Lagard et al. Database (Oxford). 2022.

. 2022 Aug 12:2022:baac062.

doi: 10.1093/database/baac062.

Authors

Affiliations

¹ Department of Microbiology and Cell Sciences, University of Florida, Gainesville, FL 32611, USA.
² Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
³ Department of Computer and Information Sciences, University of Delaware, Newark, DE 19713, USA.
⁴ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton CB10 1SD, UK.
⁵ US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁶ Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
⁷ Swiss-Prot group, SIB Swiss Institute of Bioinformatics, Centre Medical Universitaire, Geneva 4 CH-1211, Switzerland.
⁸ RCSB Protein Data Bank, Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
⁹ Departmenf of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
¹⁰ Spanish National Research Council, Institute for Integrative Systems Biology, Paterna, Valencia 46980, Spain.
¹¹ TUM (Technical University of Munich) Department of Informatics, Bioinformatics & Computational Biology, i12, Boltzmannstr. 3, Garching/Munich 85748, Germany.
¹² School of Biomedical Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, SAR Hong Kong 999077, China.
¹³ Research Collaboration Unit, Elsevier, Jericho, VT 05465, USA.
¹⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
¹⁵ Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL 32610, USA.
¹⁶ NYU-Shanghai, Shanghai 200120, China.
¹⁷ Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA.
¹⁸ Institute for Genomic Biology and Departments of Biochemistry and Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
¹⁹ Physics of Living Systems, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
²⁰ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
²¹ Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL 60439, USA.
²² Bioinformatics Research Group, SRI International, Menlo Park, CA 94025, USA.
²³ National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), National Institutes of Health (NIH), 8600 Rockville Pike, Bethesda, MD 20817, USA.
²⁴ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA.
²⁵ Plant Biology Section, School of Integrative Plant Science, Cornell University, Ithaca, NY 14853, USA.
²⁶ Department of Agricultural Education and Communication, University of Florida, Gainesville, FL 32611, USA.
²⁷ Georgetown University Medical Center, Washington, DC 20007, USA.
²⁸ Biological Sciences Division, Pacific Northwest National Laboratories, Richland, WA 99354, USA.
²⁹ School of Biotechnology and Biomolecular Sciences, University of NSW, Sydney, NSW 2052, Australia.
³⁰ Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
³¹ New England Biolabs, Ipswich, MA 01938, USA.
³² Khoury College of Computer Sciences, Northeastern University, Boston, MA 02115, USA.
³³ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
³⁴ Department of Bioengineering, Division of Engineering, University of California at San Diego, La Jolla, CA 92093-0412, USA.
³⁵ Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
³⁶ Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
³⁷ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA 90033, USA.
³⁸ Center for Biological Data Science, Virginia Commonwealth University, Richmond, VA 23284, USA.
³⁹ LABGeM, Génomique Métabolique, CEA, Genoscope, Institut François Jacob, Université d'Évry, Université Paris-Saclay, CNRS, Evry 91057, France.
⁴⁰ Department of Plant Pathology, University of Florida Citrus Research and Education Center, 700 Experiment Station Rd., Lake Alfred, FL 33850, USA.
⁴¹ Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.

PMID: 35961013
PMCID: PMC9374478
DOI: 10.1093/database/baac062

Abstract

Over the last 25 years, biology has entered the genomic era and is becoming a science of 'big data'. Most interpretations of genomic analyses rely on accurate functional annotations of the proteins encoded by more than 500 000 genomes sequenced to date. By different estimates, only half the predicted sequenced proteins carry an accurate functional annotation, and this percentage varies drastically between different organismal lineages. Such a large gap in knowledge hampers all aspects of biological enterprise and, thereby, is standing in the way of genomic biology reaching its full potential. A brainstorming meeting to address this issue funded by the National Science Foundation was held during 3-4 February 2022. Bringing together data scientists, biocurators, computational biologists and experimentalists within the same venue allowed for a comprehensive assessment of the current state of functional annotations of protein families. Further, major issues that were obstructing the field were identified and discussed, which ultimately allowed for the proposal of solutions on how to move forward.

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Figures

**Figure 1.**
Different existing resources to separate isofunctional families. The top three panels show different methods based on sequence similarities to try and identify subgroups. The bottom panel focuses on rule-based approaches. (A) SSN example from RadicalSAM.org with protein as nodes linked by an edge if they are similar within a certain threshold that shows the separation of the members of the Radical SAM superfamily; some subgroups cannot be separated as seen in Megaclusters 1–5; some are distinct as seen in Clusters 6–10; (B) network representation of the HIGH-signature proteins, UspA, and PP-ATPase (HUP) Superfamily (CATH 3.40.50.620) showing available functional annotations in FunFams. The colored nodes indicate FunFams annotated with different EC numbers, and the gray nodes indicate FunFams without any EC annotation, which includes nonenzymes [Figure from (127)]; (C) GO Phylogenetic Annotation: annotations of gains and losses of functions on ancestral nodes in the tree, based on experimental annotations (left) lead to different function annotations of uncharacterized proteins depending on their evolutionary history (right); (D) UniRule generation platform.

**Figure 2.**
(A) RCSB PDB converts global data into global knowledge. (B) INDRA performs knowledge assembly from the biomedical literature and expert-curated databases into a knowledge base of mechanistic statements that can be converted into models and networks and queried through human–machine dialogue.

**Figure 3.**
Using phylogenetic relationships to guide the integration of data associated with related proteins, mining of genomic and post-genomic data can seed defined hypotheses for the discovery of molecular and biological functions associated with genes/proteins of unknown or uncertain function.

**Figure 4.**
Questions discussed during the five sessions.

See this image and copyright information in PMC

References

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A roadmap for the functional annotation of protein families: a community perspective

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A roadmap for the functional annotation of protein families: a community perspective

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