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Engineering structural variants to interrogate genome function

Nature Genetics volume 56, pages 2623–2635 (2024)Cite this article

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Abstract

Structural variation, such as deletions, duplications, inversions and complex rearrangements, can have profound effects on gene expression, genome stability, phenotypic diversity and disease susceptibility. Structural variants can encompass up to millions of bases and have the potential to rearrange substantial segments of the genome. They contribute considerably more to genetic diversity in human populations and have larger effects on phenotypic traits than point mutations. Until recently, our understanding of the effects of structural variants was driven mainly by studying naturally occurring variation. New genome-engineering tools capable of generating deletions, insertions, inversions and translocations, together with the discovery of new recombinases and advances in creating synthetic DNA constructs, now enable the design and generation of an extended range of structural variation. Here, we discuss these tools and examples of their application and highlight existing challenges that will need to be overcome to fully harness their potential.

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Fig. 1: Tools for generating structural variants.
Fig. 2: Generating structural variants from nicked DNA with prime editing.
Fig. 3: Sequence rearrangements mediated by tyrosine and serine recombinases.
Fig. 4: Stochastically rearranged regions, chromosomes and genomes.

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Acknowledgements

We thank T. Ellis and members of the Parts laboratory for comments on the text. All authors were supported by Wellcome (220540/Z/20/A).

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  1. Wellcome Sanger Institute, Hinxton, UK

    Jonas Koeppel, Juliane Weller, Thomas Vanderstichele & Leopold Parts

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  1. Jonas Koeppel
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  2. Juliane Weller
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  3. Thomas Vanderstichele
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  4. Leopold Parts
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J.K., J.W., T.V. and L.P. drafted the initial version; J.K. and J.W. created the figures; J.K., J.W., T.V. and L.P. wrote the text.

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Correspondence to Leopold Parts.

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Koeppel, J., Weller, J., Vanderstichele, T. et al. Engineering structural variants to interrogate genome function. Nat Genet 56, 2623–2635 (2024). https://doi.org/10.1038/s41588-024-01981-7

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