Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

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Insertional Mutagenesis in Zebrafish Identifies a Diversity of Genes Required for Vertebrate Development

Nancy Hopkins
Massachusetts Institute of Technology, Cambridge, MA 02138 USA
Telephone: 617-253-6414
Fax: 617-258-0258

It has been estimated from large chemical mutagenesis screens in zebrafish that approximately 2400 genes can be mutated to yield a developmental defect visible by low power microscopy during the first 5 days of zebrafish life. In order to rapidly identify a substantial fraction of these essential genes and provide an unbiased view of the diversity of genes required for vertebrate development we performed a large insertional mutagenesis screen in zebrafish using mouse retroviral vectors as the mutagen. As was observed in chemical mutagenesis screens, mutations in about a third of these genes lead to relatively specific developmental defects involving one or a few organs, while mutations in the remaining two-thirds result in relatively non-specific phenotypes or syndromes. The latter may be genes required in many or all cell types, while the former may be genes required for the patterning, differentiation, and physiology of specific cell types or organs. We have isolated mutants in about 450-500 different genes, roughly 15-20% of those that can be identified by this approach, and have identified about 250 of the mutated genes. These genes encode proteins with a wide variety of biochemical functions, from "classical" developmental roles such as intercellular signaling and the control of cell-type-specific gene expression to roles in basic cell biological processes such as mitosis, protein synthesis, and vesicle trafficking. Furthermore, about 20% of the genes are novel, in that the biochemical function of the proteins they encode can not be predicted with certainty if at all from their amino acid sequences. All of the genes have orthologues or related sequences in human and mouse, often in fly and worm, and sometimes in yeast. Our screen demonstrates the power of forward genetics using insertional mutagenesis to assist in rapidly assigning in vivo functions to essential vertebrate genes, and it is providing a more comprehensive view of the genetic basis of vertebrate development.

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