68: Indels Enable One-Step Antiviral Innovation in TRIM5a

Tenthorey JL et al., Cell Genomics - This episode examines a study showing that insertion/deletion mutations (indels) in the v1 loop of the antiviral protein TRIM5a can create new viral specificities in a single step, whereas missense mutations often cannot. The authors used saturation missense mutagenesis, combinatorial libraries, and a novel deep indel scanning approach to compare evolutionary potential. Key terms: TRIM5a, indels, deep mutational scanning, SIVsab, antiviral evolution.

Study Highlights:
The authors performed saturation missense mutagenesis and a novel deep indel scanning of the TRIM5a v1 loop to compare mutational routes to new antiviral specificity. No single missense mutation enabled human TRIM5a to restrict SIVsab, and combinatorial sampling showed six specific changes were required to recapitulate rhesus-like activity. In contrast, a single in-frame duplication of phenylalanine (F339dup) conferred potent SIVsab restriction and broadened activity to other lentiviruses. Naturally occurring primate TRIM5a indels similarly confer novel specificities, demonstrating indels as a distinct source of evolutionary innovation.

Conclusion:
In-frame indel mutations in disordered virus-binding loops can enable rapid, large-effect gains in antiviral function that are inaccessible to single amino-acid substitutions, and such indels have contributed to TRIM5a evolution across primates.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations

First author:
Tenthorey JL

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100818

Reference:
Tenthorey JL, del Banco S, Ramzan I, Klingenberg H, Liu C, Emerman M, Malik HS. Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations. Cell Genomics. 2025;5:100818. doi: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 License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/indels-antiviral-evolution-trim5a-68

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-07.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive auditing of TRIM5a v1 loop mutagenesis results, missense vs. indel contrasts, the F339dup indel finding, and the evolutionary history of indels in primates, including biophysical interpretation and limitations.
- transcript topics: TRIM5a v1 loop and lentiviral restriction; Missense mutational scanning (DMS) vs indel mutational potential; Deep indel scanning (DIS) and the F339dup finding; Natural primate TRIM5a indels and evolutionary history; Biophysical interpretation: entropic penalty and loop pre-folding; Evolutionary implications for antiviral specificity

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 3
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Missense mutations in the TRIM5a v1 loop do not confer SIVsab restriction in human TRIM5a
- A single in-frame indel (F339dup) enables...