The zebrafish reference genome sequence and its relationship to the human genome.
Open accessAbstract
A high-quality sequence assembly of the zebrafish genome reveals the largest gene set of any vertebrate and provides information on key genomic features, and comparison to the human reference genome shows that approximately 70% of human protein-coding genes have at least one clear zebrafish orthologue. The genome of the zebrafish — a key model organism for the study of development and human disease — has now been sequenced and published as a well-annotated reference genome. Zebrafish turns out to have the largest gene set of any vertebrate so far sequenced, and few pseudogenes. Importantly for disease studies, comparison between human and zebrafish sequences reveals that 70% of human genes have at least one obvious zebrafish orthologue. A second paper reports on an ongoing effort to identify and phenotype disruptive mutations in every zebrafish protein-coding gene. Using the reference genome sequence along with high-throughput sequencing and efficient chemical mutagenesis, the project's initial results — covering 38% of all known protein-coding genes — they describe phenotypic consequences of more than 1,000 alleles. The long-term goal is the creation of a knockout allele in every protein-coding gene in the zebrafish genome. All mutant alleles and data are freely available at go.nature.com/en6mos . Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3,4,5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
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The number of sites of crucial functional importance may be unexpectedly constant across taxa, despite differences in the number of genes and the length of coding regions.
“our finding highlights another aspect: the number of sites of crucial functional importance may be unexpectedly constant across taxa, despite the differences in the number of genes and the length of the coding regions (Alexander et al. 2010; Howe et al. 2013).”
From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Howe et al. 2013
In the comparative-genomics passage (labeled Abstract; page unavailable), Howe et al. report a relatively stable number of protein-coding genes among vertebrates and a shared core that probably approximates an essential set. The paper does not establish that the number of crucial functional sites is constant across taxa, or relate such a count to differences in coding-region length. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApproximately 82% of human disease-related genes have at least one zebrafish orthologue.
“Zebrafish have become an effective and popular model organism for drug screening, drug efficacy evaluation, and dissecting molecular mechanisms of drug action, as approximately 82% of human disease-related genes have at least one zebrafish orthologue [39].”
A high-quality genome and a common SNP VCF file are available for zebrafish.
“Two useful resources for applying SNP-based demultiplexing are available for zebrafish, a high-quality genome (Howe et al, 2013), and a common SNP variant, variant call format (VCF) file for the species (LaFave et al, 2014).”
From Evaluation of genetic demultiplexing of single-cell sequencing data from model species (2023) · cites this paper as Howe et al, 2013
The predicted genome size of Danionella translucida is around one half of the zebrafish reference genome.
“The predicted genome size of DT is around one half of the zebrafish reference genome33.”
From Hybrid genome assembly and annotation of Danionella translucida (2019) · cites this paper as [33]
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- Authors
- Howe, K., Clark, M. D., Torroja, C. F., Torrance, J., Berthelot, C., Muffato, M., Collins, J. E., Humphray, S., McLaren, K., Matthews, L., McLaren, S., Sealy, I., Caccamo, M., Churcher, C., Scott, C., Barrett, J. C., Koch, R., Rauch, G.-J., White, S., Chow, W., Kilian, B., Quintais, L. T., Guerra-Assunção, J. A., Zhou, Y., Gu, Y., Yen, J., Vogel, J.-H., Eyre, T., Redmond, S., Banerjee, R., Chi, J., Fu, B., Langley, E., Maguire, S. F., Laird, G. K., Lloyd, D., Kenyon, E., Donaldson, S., Sehra, H., Almeida-King, J., Loveland, J., Trevanion, S., Jones, M., Quail, M., Willey, D., Hunt, A., Burton, J., Sims, S., McLay, K., Plumb, B., Davis, J., Clee, C., Oliver, K., Clark, R., Riddle, C., Elliott, D., Threadgold, G., Harden, G., Ware, D., Begum, S., Mortimore, B., Kerry, G., Heath, P., Phillimore, B., Tracey, A., Corby, N., Dunn, M., Johnson, C., Wood, J., Clark, S., Pelan, S., Griffiths, G., Smith, M., Glithero, R., Howden, P., Barker, N., Lloyd, C., Stevens, C., Harley, J., Holt, K., Panagiotidis, G., Lovell, J., Beasley, H., Henderson, C., Gordon, D., Auger, K., Wright, D., Collins, J., Raisen, C., Dyer, L., Leung, K., Robertson, L., Ambridge, K., Leongamornlert, D., McGuire, S., Gilderthorp, R., Griffiths, C., Manthravadi, D., Nichol, S., Barker, G., Whitehead, S., Kay, M., Brown, J., Murnane, C., Gray, E., Humphries, M., Sycamore, N., Barker, D., Saunders, D., Wallis, J., Babbage, A., Hammond, S., Mashreghi-Mohammadi, M., Barr, L., Martin, S., Wray, P., Ellington, A., Matthews, N., Ellwood, M., Woodmansey, R., Clark, G., Cooper, J. D., Tromans, A., Grafham, D., Skuce, C., Pandian, R., Andrews, R., Harrison, E., Kimberley, A., Garnett, J., Fosker, N., Hall, R., Garner, P., Kelly, D., Bird, C., Palmer, S., Gehring, I., Berger, A., Dooley, C. M., Ersan-Ürün, Z., Eser, C., Geiger, H., Geisler, M., Karotki, L., Kirn, A., Konantz, J., Konantz, M., Oberländer, M., Rudolph-Geiger, S., Teucke, M., Lanz, C., Raddatz, G., Osoegawa, K., Zhu, B., Rapp, A., Widaa, S., Langford, C., Yang, F., Schuster, S. C., Carter, N. P., Harrow, J., Ning, Z., Herrero, J., Searle, S. M. J., Enright, A., Geisler, R., Plasterk, R. H. A., Lee, C., Westerfield, M., de Jong, P. J., Zon, L. I., Postlethwait, J. H., Nüsslein-Volhard, C., Hubbard, T. J. P., Crollius, H. R., Rogers, J., & Stemple, D. L.
- Affiliations
- Wellcome Sanger Institute (GB)
- Norwich Research Park (GB)
- Centre National de la Recherche Scientifique (FR)
- European Bioinformatics Institute (GB)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- Max Planck Institute for Developmental Biology (DE)
- Dana-Farber Cancer Institute (US)
- University of Oregon (US)
- Karlsruhe Institute of Technology (DE)
- Brigham and Women's Hospital (US)
- Corresponding author
- Stemple, Derek L.
- ORCID
- Howe, Kerstin
- Clark, Matthew D.
- Torroja, Carlos F.
- Torrance, James
- Berthelot, Camille
- Muffato, Matthieu
- Collins, John E.
- Humphray, Sean
- McLaren, Stuart
- Sealy, Ian
- Barrett, Jeffrey C.
- White, Simon
- Chow, William
- Kilian, Britt
- Zhou, Yi
- Gu, Yong
- Yen, Jennifer
- Eyre, Tina
- Redmond, Seth
- Banerjee, Ruby
- Fu, Beiyuan
- Maguire, Sean F.
- Laird, Gavin K.
- Lloyd, David
- Kenyon, Emma
- Donaldson, Sarah
- Loveland, Jane
- Trevanion, Stephen
- Hunt, Adrienne
- Sims, Sarah
- Clark, Richard
- Threadgold, Glen
- Begum, Sharmin
- Kerry, Giselle
- Tracey, Alan
- Dunn, Matthew
- Wood, Jonathan
- Pelan, Sarah
- Smith, Michelle
- Harley, Joanna
- Collins, Joanna
- Leongamornlert, Daniel
- Barker, Gary
- Gray, Emma
- Saunders, David
- Martin, Sancha
- Cooper, James D.
- Andrews, Robert
- Fosker, Nigel
- Kelly, Daniel
- Dooley, Christopher M.
- Konantz, Martina
- Raddatz, Günter
- Osoegawa, Kazutoyo
- Zhu, Baoli
- Widaa, Sara
- Langford, Cordelia
- Yang, Fengtang
- Schuster, Stephan C.
- Harrow, Jennifer
- Ning, Zemin
- Herrero, Javier
- Enright, Anton
- Geisler, Robert
- Plasterk, Ronald H. A.
- Lee, Charles
- Westerfield, Monte
- Zon, Leonard I.
- Postlethwait, John H.
- Hubbard, Tim J. P.
- Crollius, Hugues Roest
- Stemple, Derek L.
- Venue
- Nature
- Published
- 2013-04-17
- Volume
- 496
- Issue
- 7446
- Pages
- 498-503
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3703927
- OpenAlex
- W1981239255
- Cited by
- 5,100
- References
- 31
- Citations by year
- 2026: 373 · 2025: 502 · 2024: 508 · 2023: 461 · 2022: 530 · 2021: 524 · 2020: 415 · 2019: 379 · 2018: 325 · 2017: 305 · 2016: 268 · 2015: 203 · 2014: 220 · 2013: 76 · 2012: 1
- FWCI
- 148.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-12-11)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Cronfa (Swansea University) (submittedVersion, cc-by-nc-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, other-oa)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Wellcome Trust (095908, grant number 098051, 098051)
- European Commission (242048, LSHG-CT-2003-503496)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (R01OD011116, HD22486)
- Biotechnology and Biological Sciences Research Council (BBS/E/T/000PR5885, BBS/E/T/000PR6193)
- National Institute of General Medical Sciences (R01GM085318)
- National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK55377-01A1, R01DK055377)
- National Center for Research Resources (R01RR020833, R01RR010715)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD022486, P01 HD22486)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- zebrafish genome, genome assembly, human orthologs, pseudogenes, repetitive DNA, genome annotation, knockout alleles, mutant phenotypes, chemical mutagenesis, comparative genomics, vertebrate evolution, zebrafish disease models, zebrafish development
- MeSH terms
- Animals, Chromosomes, Female, Genes, Humans, Male, Meiosis, Pseudogenes, Reference Standards, Zebrafish, Genome, Human, Genome, Conserved Sequence, Evolution, Molecular, Sex Determination Processes, Genomics, Zebrafish Proteins, Molecular Sequence Annotation
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