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Fishing for Answers in Human Disease

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Images of both a wild type zebrafish and a vhnf1 mutant zebrafish. The mutant fish shows abnormal bulging in its upper body.

Caption: Researcher Zhaoxia Sun, at Yale, uses the zebrafish to study Polycystic Kidney Disease, which affects more than 600,000 Americans. Mutations in the zebrafish vhnf1 gene, and its human counterpart, cause cysts in both zebrafish and human kidneys (as shown by the large “bubble” seen in the mutant fish). [3]
Credit: Zhoaxia Sun, Biological & Biomedical Sciences, Yale University

Wouldn’t it be instructive if we could see the effect of a genetic mutation in real time, as the gene was misbehaving? Well, that’s one of the perks of using the zebrafish—a tiny, striped, transparent fish.

Just last month, an international team of scientists—funded in part by NIH—published the entire genetic code of the zebrafish [1]. This is a vital resource for understanding human health and disease. How does the genetic blueprint of a fish help us or accelerate drug discovery? Well, it turns out that more than 75% of the genes that have been implicated in human diseases have counterparts in the zebrafish. So, if we discover a mutation in a human, we can make the corresponding mutation in the zebrafish gene—and often get a pretty good idea of how the gene works, how the mutation causes havoc, and how it causes disease in humans. We can even use the zebrafish to test potential drug candidates, to see whether they can alter or fix the symptoms before moving on to mice or humans.

A second paper in the same issue of Nature describes how another team has created mutations in 38% of all the zebrafish genes and is now investigating the effects of each mutation [2]. Fishy as it sounds, it’s an amazing system to learn about biology.

References:

[1] The zebrafish reference genome sequence and its relationship to the human genomeHowe K, et al. Nature. 2013 Apr 25;496(7446):498-503. doi: 10.1038/nature12111. Epub 2013 Apr 17.

[2] A systematic genome-wide analysis of zebrafish protein-coding gene function. Kettleborough RN, Busch-Nentwich EM, Harvey SA, Dooley CM, de Bruijn E, van Eeden F, Sealy I, White RJ, Herd C, Nijman IJ, Fényes F, Mehroke S, Scahill C, Gibbons R, Wali N, Carruthers S, Hall A, Yen J, Cuppen E, Stemple DL. Nature. 2013 Apr 25;496(7446):494-7.

Genomics: Zebrafish earns its stripes. Schier AF. Nature. 2013 Apr 25;496(7446):443-4.

[3] vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Sun Z, Hopkins N.  Genes Dev. 2001 Dec 1;15(23):3217-29.

NIH support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; Office of the Director