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Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

Nature Reviews Genetics volume 25, pages 46–60 (2024)Cite this article

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Abstract

Next-generation sequencing technology has rapidly accelerated the discovery of genetic variants of interest in individuals with rare diseases. However, showing that these variants are causative of the disease in question is complex and may require functional studies. Use of non-mammalian model organisms — mainly fruitflies (Drosophila melanogaster), nematode worms (Caenorhabditis elegans) and zebrafish (Danio rerio) — enables the rapid and cost-effective assessment of the effects of gene variants, which can then be validated in mammalian model organisms such as mice and in human cells. By probing mechanisms of gene action and identifying interacting genes and proteins in vivo, recent studies in these non-mammalian model organisms have facilitated the diagnosis of numerous genetic diseases and have enabled the screening and identification of therapeutic options for patients. Studies in non-mammalian model organisms have also shown that the biological processes underlying rare diseases can provide insight into more common mechanisms of disease and the biological functions of genes. Here, we discuss the opportunities afforded by non-mammalian model organisms, focusing on flies, worms and fish, and provide examples of their use in the diagnosis of rare genetic diseases.

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Fig. 1: The role of model organisms in the genetic diagnosis of rare human diseases.
Fig. 2: Genetic approaches to studying gene function in Caenorhabditis elegans and Danio rerio.
Fig. 3: Genetic approaches to studying gene function in Drosophila melanogaster.
Fig. 4: From rare diseases to common diseases.

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Acknowledgements

The authors thank L. Burrage, J. Mokry, G. Lin, X. Pan, M. Moulton, L. Goodman and S. Lu for suggestions on this manuscript. They also thank P. Hieter, K. Boycott, P. Campeau and C. Oriel for proving valuable information regarding the RDMM, P. Marcogliese for help with analysis of the literature, and Y. Hu for providing data regarding DIOPT.

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  1. These authors contributed equally: Shinya Yamamoto, Oguz Kanca.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Shinya Yamamoto, Oguz Kanca, Michael F. Wangler & Hugo J. Bellen

  2. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Shinya Yamamoto, Oguz Kanca, Michael F. Wangler & Hugo J. Bellen

  3. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Shinya Yamamoto & Hugo J. Bellen

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Related links

Alliance of Genome Resources: https://www.alliancegenome.org/

Drosophila RNAi Screening Center (DRSC) Integrative Orthologue Prediction Tool: https://www.flyrnai.org/diopt

GeneMatcher: https://genematcher.org/

Genome Aggregation Database: https://gnomad.broadinstitute.org/

MARRVEL: https://marrvel.org/

Matchmaker Exchange: https://www.matchmakerexchange.org/

ModelMatcher: https://www.modelmatcher.net/

Monarch Initiative Explorer: https://monarchinitiative.org/

Online Mendelian Inheritance in Man: https://www.omim.org/

PhenomeCentral: https://www.phenomecentral.org/

Rare Disease Models and Mechanisms: https://www.rare-diseases-catalyst-network.ca/

Undiagnosed Diseases Network: https://undiagnosed.hms.harvard.edu/

Supplementary information

Glossary

Amorphic allele

An allele that abrogates gene function, also known as a null allele or a complete loss-of-function allele.

Antimorphic allele

An allele that alters the function of the protein and interferes with its normal function, typically by affecting proteins that it normally interacts with. Also known as a dominant negative allele.

GAL4/UAS system

An essential genetic strategy used primarily in Drosophila melanogaster to overexpress a transgene under the control of UAS regulatory elements by expressing GAL4, typically under the control of specific enhancers.

Hypermorphic allele

An allele that increases the function of the gene product through either increased expression or increased activity. Also known as a gain-of-function allele.

Hypomorphic allele

An allele that partially impairs the function of the gene. Also known as a partial loss-of-function allele.

Kozak–GAL4 cassette

A genetic construct that replaces the coding region of the targeted gene with the gene encoding GAL4. Expression of GAL4 is enhanced by the presence of the Kozak consensus sequence to improve translation.

Mos1-mediated single copy insertion

A homologous recombination-based method in Caenorhabditis elegans to integrate a single copy of a transgene in a locus based on Mos1 transposon mobilization.

Neomorphic allele

An allele that confers a new function, different from the original function of the gene.

P[acman]

A plasmid that has a constitutive, low copy number origin of replication and an inducible, high copy number origin of replication. The design allows large constructs (such as bacterial artificial chromosomes) to be altered through recombineering at a low copy number state and to obtain large amounts of engineered plasmids to be prepped for transgenesis and injection in embryos.

phiC31-mediated transgenesis

A genetic strategy that repurposes an integrase from phiC31 bacteriophage to allow single copy integration of transgenes in predefined loci. It also allows transgenesis with larger constructs than for transposon-based methods (such as P-element, PiggyBac or Minos).

T2A–GAL4 cassette

A genetic construct (SA–T2A–GAL4–polyA) that functions as an artificial exon when inserted in an intron between two exons. It causes premature termination of transcription. During translation, the protein chain is broken at the T2A site and an untethered GAL4 protein is produced.

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Yamamoto, S., Kanca, O., Wangler, M.F. et al. Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans. Nat Rev Genet 25, 46–60 (2024). https://doi.org/10.1038/s41576-023-00633-6

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