Modelling human genetic disorders in xenopus tropicalis: a practical guide

Abstract

Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic variants being identified demands in vivo model systems that are amenable to functional analyses at scale. Here we provide a practical guide for using the diploid frog species Xenopus tropicalis to study many genes and variants in parallel, thus uncovering conserved mechanisms of pathobiology relevant to human disease. Much of this work requires Xenopus labs to adopt an altered strategy, moving from focusing on a specific developmental process to being responsive to human gene variant discovery. We discuss key considerations in modeling human genetic disorders: genetic architecture, phenotyping strategy and rigor, as well as more complex topics such as penetrance, expressivity, sex differences and current challenges in the field. As patient-driven gene discovery expands significantly, the cost-effective, rapid, and higher-throughput nature of Xenopus models makes it an essential member of the model organism armamentarium for understanding gene function in development and in relation to disease.

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Identifiers

ORCID for Eleanor G. Seaby: orcid.org/0000-0002-6814-8648

ORCID for Sarah Ennis: orcid.org/0000-0003-2648-0869

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