Zebrafish: A Model System to Study the Architecture of Human Genetic Disease

The current ability to sequence whole exomes and genomes has reached an unprecedented pace. Variant data have been cataloged for >1 M individuals representative of Mendelian disease cohorts, complex trait consortia, and healthy populations. This flood of information, expected to grow hyperexponentially in the coming years, has already fuelled the development of animal models to assign physiological relevance of genotype to phenotype; to inform variant pathogenicity; and to dissect multilocus interactions. Here, we discuss zebrafish as a robust model system that offers similar genomic and anatomical orthology to humans, with the added advantages of experimental tractability and a refined set of molecular tools that enable scalable throughput analyses. We will compare and contrast zebrafish to other animal model systems; provide a historical perspective on zebrafish forward and reverse genetics; and we will overlay the relative strengths and weaknesses of the model to interpret pathomechanism of germline mutations in humans.