️ 68: Indels Empower Antiviral Proteins to Achieve Functional Novelty Beyond Missense Mutations

️ Episode 68: Indels Empower Antiviral Proteins to Achieve Functional Novelty Beyond Missense Mutations In this episode of Base by Base, we dive into pioneering work by Tenthorey et al. (2025) in Cell Genomics that uncovers how insertion and deletion mutations—indels—can unlock evolutionary innovations in the antiviral protein TRIM5α. By applying both deep mutational scanning and a novel deep indel scanning approach to the v1 loop of human TRIM5α, the authors reveal that while no single-nucleotide missense change can confer restriction of the simian immunodeficiency virus SIVsab, a single in-frame duplication of phenylalanine at position 339 instantaneously grants potent antiviral activity against SIVsab and other lentiviruses. This discovery highlights indels as a powerful, yet often overlooked, mechanism for traversing otherwise insurmountable fitness landscapes in host–virus evolutionary arms races. Study Highlights: In exhaustive screens, human TRIM5α variants bearing every possible missense change failed to inhibit SIVsab, underscoring the limits of point mutations. Deep indel scanning then identified three in-frame duplication variants that gained SIVsab restriction, with the F339dup alone replicating nine independent rhesus-like mutations in one step. This single amino acid duplication not only enabled defense against SIVsab but also broadened activity to HIV-1 and SIVcpz without impairing existing N-tropic murine leukemia virus restriction, demonstrating a net evolutionary gain. Comparative analysis of primate TRIM5α orthologs confirmed that naturally occurring indels—such as a two-residue insertion in rhesus monkeys and a 20-residue duplication in sabaeus monkeys—directly determine species-specific antiviral specificities. Conclusion: By revealing that indel mutations can deliver high-risk, high-reward leaps in protein function inaccessible by missense changes alone, this work reshapes our understanding of antiviral adaptation. Indels emerge not as mere byproducts of genetic drift but as strategic evolutionary tools that enable rapid, robust innovation in host defenses. Reference: Tenthorey, J. L., del Banco, S., Ramzan, I., Klingenberg, H., Liu, C., Emerman, M., & Malik, H. S. (2025). Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations. Cell Genomics, 5, 100818. https://doi.org/10.1016/j.xgen.2025.100818 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

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