Zebrafish mutations and functional analysis of the vertebrate genome.

As the first draft of the human genome nears completion, we are faced with the challenge of defining the functions of the 70,000–100,000 genes contained within the sequence. A powerful combination of large-scale forward genetics and elegant cellular analysis ensures that the zebrafish will have an important role in the functional analysis of the vertebrate genome. Genetic screens have identified mutations that define the functions of hundreds of essential genes—a number that will increase considerably as ongoing screens search for previously unexplored mutant phenotypes (Driever et al. 1996; Haffter et al. 1996). The functions of mutated genes can be examined at the cellular level by sophisticated phenotypic analysis, such as lineage tracing and cellular transplantation, of mutant embryos (Kimmel 1989). Thus, the facile genetics of zebrafish allows the rapid isolation of mutations, and phenotypic analysis can reveal gene functions that are difficult to uncover in other systems. Over the past several years strategies to clone mutated genes have been developed, and ongoing efforts to improve the genomics infrastructure for the zebrafish will accelerate the molecular analysis of zebrafish mutations. Here we review some recent advances in genomic resources that will augment the cloning of mutated zebrafish genes by positional cloning, the candidate gene approach, and insertional mutagenesis.