The goal of this proposal is to facilitate comparisons among various models of vertebrate development by increasing the connections that can be made between the genomes of mammals and the genome of the zebrafish, Danio rerio. In zebrafish, saturation mutagenesis can identify mutations in nearly all genes essential for any process of interest. Mutant phenotypes can be analyzed in zebrafish at the single cell level in the nervous system, somites, heart, notochord, and other organs shared by all vertebrates. Development of these organs is very similar at the genetic, cellular, and organ levels in embryos of zebrafish and other vertebrates, including mammals. Furthermore, segments of the genetic maps of zebrafish and mammals may have been conserved throughout vertebrate evolution. These genetic, phenotypic, and comparative features, suggest that genomic analysis in zebrafish can facilitate an understanding of genome structure and function in all vertebrates.
Specific Aim 1 is to place a large number of cloned zebrafish genes on the zebrafish genetic map. These will provide candidate genes for mutations and will delineate chromosome segments in which gene order has been conserved in vertebrate evolution.
Specific Aim 2 is to place selected additional mutations of high interest on the map in order to see if they might lie near any of the cloned genes mapped in specific aim 1.
Specific Aim 3 is to construct high density local maps around selected genes as a prelude to cloning them.
Specific Aim 4 is to associate current linkage groups to individual zebrafish chromosomes and to place centromeres on the genetic map in order to facilitate the analysis of chromosome rearrangements and enhance cloning efforts. Accomplishing these specific aims will improve our ability to clone zebrafish genes identified by mutation and will identify chromosome segments in which gene orders have been conserved in vertebrate evolution. Knowing the function of zebrafish mutations mapped to conserved chromosome segments may make apparent candidate genes for human hereditary disorders of unknown mechanism. Because zebrafish mutations include those that mimic human genetic disease; that block conserved processes in vertebrate development; and that interfere with the functioning of specific organs including heart, brain, and intestinal tract, achieving the specific aims will enhance our understanding of human disease.
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