A systematic genome-wide analysis of zebrafish protein-coding gene function

R.N. Kettleborough; E.M. Busch-Nentwich; S.A. Harvey; C.M. Dooley; E. de Bruijn; F. van Eeden; I. Sealy; R.J. White; C. Herd; I.J. Nijman; F. Fenyes; S. Mehroke; C. Scahill; R. Gibbons; N. Wali; S. Carruthers; A. Hall; J. Yen; E. Cuppen; D.L. Stemple

doi:10.1038/nature11992

A systematic genome-wide analysis of zebrafish protein-coding gene function

R.N. Kettleborough, E.M. Busch-Nentwich, S.A. Harvey, C.M. Dooley, E. de Bruijn, F. van Eeden, I. Sealy, R.J. White, C. Herd, I.J. Nijman, F. Fenyes, S. Mehroke, C. Scahill, R. Gibbons, N. Wali, S. Carruthers, A. Hall, J. Yen, E. Cuppen, D.L. Stemple

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

501 Citations (Scopus)

Abstract

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

Original language	English
Pages (from-to)	494-497
Journal	Nature
Volume	496
Issue number	7446
DOIs	https://doi.org/10.1038/nature11992
Publication status	Published - 2013

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Kettleborough, R. N., Busch-Nentwich, E. M., Harvey, S. A., Dooley, C. M., de Bruijn, E., van Eeden, F., Sealy, I., White, R. J., Herd, C., Nijman, I. J., Fenyes, F., Mehroke, S., Scahill, C., Gibbons, R., Wali, N., Carruthers, S., Hall, A., Yen, J., Cuppen, E., & Stemple, D. L. (2013). A systematic genome-wide analysis of zebrafish protein-coding gene function. Nature, 496(7446), 494-497. https://doi.org/10.1038/nature11992

@article{609cc02390324a838b41d550aea36368,

title = "A systematic genome-wide analysis of zebrafish protein-coding gene function",

abstract = "Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.",

author = "R.N. Kettleborough and E.M. Busch-Nentwich and S.A. Harvey and C.M. Dooley and {de Bruijn}, E. and {van Eeden}, F. and I. Sealy and R.J. White and C. Herd and I.J. Nijman and F. Fenyes and S. Mehroke and C. Scahill and R. Gibbons and N. Wali and S. Carruthers and A. Hall and J. Yen and E. Cuppen and D.L. Stemple",

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Kettleborough, RN, Busch-Nentwich, EM, Harvey, SA, Dooley, CM, de Bruijn, E, van Eeden, F, Sealy, I, White, RJ, Herd, C, Nijman, IJ, Fenyes, F, Mehroke, S, Scahill, C, Gibbons, R, Wali, N, Carruthers, S, Hall, A, Yen, J, Cuppen, E & Stemple, DL 2013, 'A systematic genome-wide analysis of zebrafish protein-coding gene function', Nature, vol. 496, no. 7446, pp. 494-497. https://doi.org/10.1038/nature11992

TY - JOUR

T1 - A systematic genome-wide analysis of zebrafish protein-coding gene function

AU - Kettleborough, R.N.

AU - Busch-Nentwich, E.M.

AU - Harvey, S.A.

AU - Dooley, C.M.

AU - de Bruijn, E.

AU - van Eeden, F.

AU - Sealy, I.

AU - White, R.J.

AU - Herd, C.

AU - Nijman, I.J.

AU - Fenyes, F.

AU - Mehroke, S.

AU - Scahill, C.

AU - Gibbons, R.

AU - Wali, N.

AU - Carruthers, S.

AU - Hall, A.

AU - Yen, J.

AU - Cuppen, E.

AU - Stemple, D.L.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

AB - Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

U2 - 10.1038/nature11992

DO - 10.1038/nature11992

M3 - Article

SN - 0028-0836

VL - 496

SP - 494

EP - 497

JO - Nature

JF - Nature

IS - 7446

ER -

A systematic genome-wide analysis of zebrafish protein-coding gene function

Abstract

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