Zebrafish: A New Model for Human Disease

摘要: Picture this—you have just mapped a human disease locus to particular region of chromosome. With click computer button, the chromosomal synteny in zebrafish (Danio rerio) genome is revealed. Behold, there are several mutant loci this general synteny. Another and you find fish resembling your disease. Further clicking reveals independent alleles with varying phenotypes establishing pathophysiology Does sound farfetched? Well, recently mutants “human” diseases been found. more infrastructure for system, above scenario could become commonplace. The an excellent system developmental biologists geneticists (Westerfield 1989; Detrich et al. 1999). externally developing embryos clear, allowing visualization organ systems. 1-inch size allows large numbers these vertebrates be maintained relatively small space. In addition, each female lays >200 eggs per week. This enables study meioses positional cloning purposes. genetic map has continually improving over past 2 years, currently >2000 microsatellite markers up 400 genes defined (Knapik 1998; Postlethwait 1998) 1.7 10-bp (M. Fishman J. Postlethwait, unpubl). was originally envisioned provide important clues normal embryogenesis development. Because it vertebrate, organism would bridge gap between Drosophila/Caenhorhabditis elegans mouse/human genetics. A flurry candidate gene-cloning experiments revealed that attractive one biology clearly demonstrates use embryonic axis early neurogenesis (Solnica-Krezel hope vertebrate relate human, define loci. Positional approaches made possible by development key reagents such as YAC, PAC, BAC libraries (Amemiya 1999), well radiation hybrid panels (Kwok M. Ekker, unpubl.). first project involved isolation one-eyed-pinhead gene (Zhang 1998), novel cell surface molecule EGF repeats. second sauternes (sau) (Brownlie 1998). Sau number blood cells circulating on day 2, but fail make hemoglobin. phenotype proved due defect erythroid synthase d-aminolevulinate (ALAS-2) gene, which regulates step heme biosynthesis red cells. Human patients ALAS-2 mutations very similar called congenital sideroblastic anemia, animal model (see Fig. 1). Additionally, Shuo Lin coworkers provided evidence yquem (yqe) uroporphyrinogen decarboxylase (UROD) deficiency (Wang equivalent porphyria further establishes case some will represent diseases. Are unique among their relevance disease? Clearly, other all resemble disorders (Driever 1996). For instance, gridlock coarctation aorta humans (Weinstein 1995). cystic kidneys may polycystic kidney (Drummond It remains clinicians examine issue Development (1996) see whether interesting known previously mouse genomes share blocks synteny, no believed structure human. many loci, obvious (Postlethwait facilitates genes, can utilize information from Genome Project. researcher scour databases look near mutation. future, should investigators studying genetics able interface directly Web site (The Zebrafish Server, Fish Net, ZFIN, http://zfish.uoregon.edu/) evaluate interest investigator. process “genome ping-ponging” based syntenic relationships establish usefulness understanding article Davidson power conserved vertebrates. GDF encode critical E-MAIL zon@rascal.med.harvard.edu; FAX (617) 355-7262. Insight/Outlook