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The status of the human gene catalogue
- Paulo Amaral1,
- Silvia Carbonell-Sala ORCID:orcid.org/0000-0001-7956-62152,
- Francisco M. De La Vega3,4,
- Tiago Faial5,
- Adam Frankish6,
- Thomas Gingeras7,
- Roderic Guigo2,8,
- Jennifer L. Harrow9,
- Artemis G. Hatzigeorgiou10,11,
- Rory Johnson ORCID:orcid.org/0000-0003-4607-278212,13,14,15,
- Terence D. Murphy ORCID:orcid.org/0000-0001-9311-974516,
- Mihaela Pertea17,18,19,
- Kim D. Pruitt16,
- Shashikant Pujar16,
- Hazuki Takahashi ORCID:orcid.org/0000-0001-7315-734920,
- Igor Ulitsky21,22,
- Ales Varabyou ORCID:orcid.org/0000-0003-1060-721217,19,
- Christine A. Wells ORCID:orcid.org/0000-0003-3133-362823,
- Mark Yandell ORCID:orcid.org/0000-0002-9497-450524,
- Piero Carninci ORCID:orcid.org/0000-0001-7202-724320,25 &
- …
- Steven L. Salzberg ORCID:orcid.org/0000-0002-8859-743217,18,19,26
Naturevolume 622, pages41–47 (2023)Cite this article
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Abstract
Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.
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Acknowledgements
We thank the staff at the Banbury Center at Cold Spring Harbor Laboratory and the Cold Spring Harbor Laboratory Corporate Sponsor Program for supporting a workshop that all authors of this work attended. This work was supported in part by the US National Institutes of Health (NIH) under grants R01-HG006677 (to M.P., S.L.S. and A.V.), R01-MH123567 (to M.P. and S.L.S.), R35-GM130151 (to S.L.S.), U41-HG007234 (to A.F.) and U24-HG007234 (to R.G. and S.C.-S.); the Wellcome Trust under grant WT222155/Z/20/Z (to A.F.); the European Molecular Biology Laboratory (to A.F.); the US National Science Foundation under grant DBI-1759518 (to M.P.); the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under grant T2EDK-00391 (to A.G.H.); Science Foundation Ireland through Future Research Leaders award 18/FRL/6194 and the Irish Research Council through Consolidator Laureate award (IRCLA/2022/2500; to R.J.); the National Center for Biotechnology Information of the National Library of Medicine, NIH (to T.D.M., K.D.P. and S.P.); the National Health and Medical Research Council (NHMRC) APP1186371 (to C.A.W.); the Center for Genomic Medicine at the University of Utah Health, and the H.A. & Edna Benning Foundation (to M.Y.); the Spanish Ministry of Science and Innovation to the EMBL partnership, Centro de Excelencia Severo Ochoa and CERCA Programme/Generalitat de Catalunya (to R.G. and S.C.-S.); the RIKEN Center for Integrative Medical Sciences (to P.C. and H.T.); and Human Technopole (to P.C.).
Author information
Authors and Affiliations
INSPER Institute of Education and Research, Sao Paulo, Brazil
Paulo Amaral
Centre for Genomic Regulation (CRG), Barcelona, Spain
Silvia Carbonell-Sala & Roderic Guigo
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
Francisco M. De La Vega
Tempus Labs, Chicago, IL, USA
Francisco M. De La Vega
Nature Genetics, San Francisco, CA, USA
Tiago Faial
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
Adam Frankish
Department of Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Thomas Gingeras
Universitat Pompeu Fabra (UPF), Barcelona, Spain
Roderic Guigo
Centre for Genomics Research, Discovery Sciences, AstraZeneca, Royston, UK
Jennifer L. Harrow
Department of Computer Science and Biomedical Informatics, Universithy of Thessaly, Lamia, Greece
Artemis G. Hatzigeorgiou
Hellenic Pasteur Institute, Athens, Greece
Artemis G. Hatzigeorgiou
School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
Rory Johnson
Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin, Ireland
Rory Johnson
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Rory Johnson
Department for BioMedical Research, University of Bern, Bern, Switzerland
Rory Johnson
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
Terence D. Murphy, Kim D. Pruitt & Shashikant Pujar
Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
Mihaela Pertea, Ales Varabyou & Steven L. Salzberg
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
Mihaela Pertea & Steven L. Salzberg
Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
Mihaela Pertea, Ales Varabyou & Steven L. Salzberg
Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Hazuki Takahashi & Piero Carninci
Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
Igor Ulitsky
Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
Igor Ulitsky
Stem Cell Systems, Department of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
Christine A. Wells
Departent of Human Genetics, Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA
Mark Yandell
Human Technopole, Milan, Italy
Piero Carninci
Department of Biostatistics, Johns Hopkins University, Baltimore, MD, USA
Steven L. Salzberg
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P.A., S.C.-S., F.M.D.L.V., T.F., A.F., T.G., R.G., J.L.H., A.G.H., R.J., T.D.M., M.P., K.D.P., S.P., H.T., I.U., A.V., C.A.W., M.Y., P.C. and S.L.S. participated in discussions at a Banbury Conference at Cold Spring Harbor Laboratory, providing the source material for this paper. All authors contributed to writing, editing and reviewing the paper.
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Correspondence toPiero Carninci orSteven L. Salzberg.
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Amaral, P., Carbonell-Sala, S., De La Vega, F.M.et al. The status of the human gene catalogue.Nature622, 41–47 (2023). https://doi.org/10.1038/s41586-023-06490-x
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Comments
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Laurence A. Moran
The best definition of a molecular gene is a DNA sequence that's transcribed to produce a functional product. (There are exceptions.) I emphasize "function," as do the authors. A DNA sequence that's merely transcribed isn't a gene, by definition, until the product has been identified with a biological function. We know that a large number of long transcripts are very likely to be spurious non-functional transcripts transcribed from junk DNA.
The problem with this paper is that the authors identify somewhere between 18,000 and 96,000 lncRNA "genes" when they must know that only a tiny subset of these transcripts have a known function and very few are conserved. (Conservations is a reasonable proxy for function.) The authors should have made a much more serious attempt to identify the small number of transcripts that are known to be functional instead of contributing to the myth that there are more noncoding genes than protein-coding genes.
Laurence A. Moran
Many very well known experts were predicting about 30,000 genes back in 1970. The final number may turn out to be about 25,000 so those experts were fairly accurate.
It's time to give those experts the credit they deserve instead of emphasizing Gilbert's back-of-the-envelope estimate of 100,000 that wasn't based on evidence - indeed, it ignored all the evidence that was available at the time.
