Directed evolution of multimeric proteins is enabled by dual-compensatory gene duplication.

Rezwan Siddiquee, Felicia Lie, Taylor N Szyszka, Alex Loustau, Michael P Andreas, Tobias W Giessen, Yu Heng Lau

Abstract readPreprint

In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it

0cells of the map it votes in

0citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

Rezwan SiddiqueeSchool of Chemistry, The University of Sydney; Camperdown, NSW 2006, Australia.

Felicia LieSchool of Chemistry, The University of Sydney; Camperdown, NSW 2006, Australia.

Taylor N SzyszkaSchool of Chemistry, The University of Sydney; Camperdown, NSW 2006, Australia.

Alex LoustauSchool of Chemistry, The University of Sydney; Camperdown, NSW 2006, Australia.

Michael P AndreasDepartment of Biological Chemistry, University of Michigan Medical School; Ann Arbor, MI 48109, USA.

Tobias W GiessenDepartment of Biological Chemistry, University of Michigan Medical School; Ann Arbor, MI 48109, USA.ORCID 0000-0001-6328-2031

Yu Heng LauSchool of Chemistry, The University of Sydney; Camperdown, NSW 2006, Australia.ORCID 0000-0001-6560-8410

Funding

Protein Organelles In Human-Associated BacteriaR35GM133325 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Tobias Wolfgang Giessen · 2019 to 2026

$3.8M

NIGMS NIH HHS R35 GM133325

6 · The paper itself

Abstract

Gene duplication has played a critical role in the evolutionary history of proteins, enabling complex multimers to emerge from simpler precursors. Yet in protein engineering, current methods for directed evolution do not exploit gene duplication, hampering access to the vast array of diverse variants that are only enriched in the presence of a wild-type copy. We establish a directed evolution strategy for multimeric proteins that harnesses gene duplication to compensate for metabolic burden and self-assembly fitness, allowing previously inaccessible variants to be enriched. Starting from a homomeric 240-mer capsid, gene duplication enables selection of both extreme homomeric variants and obligate heteromers. This strategy significantly expands engineering access to diverse high-performing variants, while also supporting a plausible model for evolutionary diversification of higher-order multimers in nature.

Identifiers

PMID41648261

DOI10.64898/2026.01.12.698938

PMCPMC12871212

What OpenQuestion holds

Textmetadata

LicenceCC BY-NC-ND

Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.