Zebrafish models human regulation and disease

The zebrafish (Danio rerio) is an important model organism for biological research, especially for studying human diseases and for drug discovery. Key features that contribute to its widespread use include its genetic amenability, its short reproduction time and its transparency, which facilitates observation of cell movement and gene expression.

The EU-funded 'Zebrafish regulomics for human health' (ZF-HEALTH) project is the continuation of the ZF-MODELS project. Researchers have used many of the technologies and tools developed during ZF-MODELS to phenotype a vast array of regulatory genes linked with human disease.

Scientists have generated transgenic fish mutated in 14 586 genes, which represents 55 % of all protein-coding genes. The current goal is to knock out every protein-coding zebrafish gene. The ongoing evaluation of behavioural phenotypes has identified more than 200 abnormal phenotypes with 4D digital reconstructions of developing embryos.

Identifying the regulatory regions of the mutated genes using bioinformatics and transgenics and comparing them with the human equivalents relevant to disease is a significant part of the work. The researchers have produced new genome-wide predictions of genomic regulatory blocks with three species (zebrafish, Tetraodon, human) as reference genomes. A genome browser has been set up showing highly conserved non-coding elements, syntenic sequences of genes conserved within chromosomes, and epigenetic markers for the entire human genome.

A considerable part of the ZF-HEALTH-generated data and images has advanced the Zebrafish brain atlas. Special software has been developed to associate anatomical parts of the brain with specific gene expression patterns and links to human diseases. Moreover, available to the scientific community, a virtual brain explorer can compare expression of large numbers of genes and map to parts of the body.

Dissemination of results continues to be widespread. In the third year of the project, consortium members gave 150 presentations at scientific conferences, workshops and external seminars and 19 presentations to the general public, and published 28 articles in peer-reviewed scientific journals. Overall, the ZF-HEALTH study holds great translational research potential and its findings could be utilised to shed light on regulatory mechanisms in humans and their implication in disease.