Xenopus as a Model Organism for the Analysis of Human Genetic Disease

Abstract

Candidate human disease alleles are being identified at a rapid pace, due to next‐generation sequencing in combination with a high‐throughput bioinformatics pipeline. The verification of gene variants as disease causing requires predictive in vivo model systems. In this respect, the frog Xenopus has great potential as a model to study human genetic diseases. Xenopus offers efficient assessment of disease‐associated genes and alleles. Gene loss‐of‐function studies frequently reproduce human disease manifestations or reveal context‐related phenotypes. Introduction of human wild‐type and mutant alleles into Xenopus embryos offers in‐depth investigations of disease‐causing mechanisms at the subcellular, cellular, tissue or organismic level. Xenopus therefore ideally complements the more frequently used mouse and zebrafish as a valid, fast and cost‐efficient vertebrate model system.

Key Concepts

  • Potential human disease genes and variants need to be assessed in predictive in vivo model systems.
  • Four out of five human disease genes have homologs in Xenopus.
  • Xenopus homologs of human disease genes can be easily manipulated in a lineage‐specific manner.
  • Xenopus can be unilaterally manipulated such that the unmanipulated side serves as an internal control.
  • Gene loss‐of‐function frequently mimics human disease states in Xenopus.
  • Human gene variants can be functionally investigated by introduction into Xenopus embryos.

Keywords: Xenopus; human syndrome; disease model; disease allele; disease variant; morpholinos; genome editing

Figure 1. Strategies to investigate human disease alleles in the frog Xenopus. (a) Gene loss‐of‐function phenotypes can be readily assessed following genome editing or MO‐mediated knockdown in Xenopus. Phenotypes may resemble the human disease condition or occur in related embryonic contexts, verifying a given gene as disease causing. (b) Introduction of the human wild‐type allele should rescue the phenotype, while disease variants should reveal lack, attenuated or increased rescue capacities, which can be used to unravel disease mechanisms at the molecular level. (c) Misexpression of candidate human disease alleles in wild‐type Xenopus embryos may reveal phenotypes, depending on the allele investigated. (d) Editing the homologous Xenopus gene to generate an allele corresponding to the human disease allows for disease modelling in a direct manner.
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Further Reading

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Ott, Tim, and Blum, Martin(May 2020) Xenopus as a Model Organism for the Analysis of Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028659]