Tuesday, 17 March 2026

Ramiro-Martínez P, Quinto I, Jaraba L, Lanza VF, Herencias C, González A, Peña R, Rodríguez J. Plasmid mutation rates scale with copy number

Proc Natl Acad Sci U S A. 2026

"Many genetic systems, including the genomes of mitochondria, plastids, cancer cells, and antimicrobial resistance plasmids exist in multiple copies. Our results shed light on a long-standing controversy and show that their high copy number translates into an enormous evolutionary potential" - Paula Ramiro-Martínez and Dr. Jerónimo Rodríguez-Beltrán

Summary:

Plasmids are extrachromosomal DNA molecules that spread by horizontal transfer and shape bacterial evolution. Plasmids are typically present at multiple copies per bacterial cell, and these extra copies increase the supply of plasmid mutations, potentially accelerating their evolution. However, the segregation of plasmid copies to daughter cells is random, introducing an additional layer of genetic drift, termed segregational drift, that might delay plasmid evolution. The interplay between plasmid mutational supply and segregational drift determines the evolutionary rate of plasmid-encoded genes, yet the relative contribution of these opposite forces in plasmid evolution remains unclear. Here, we develop a population genetics framework to predict the rate of plasmid mutations in bacterial populations and validate these predictions using computational, experimental, and bioinformatic approaches. Our findings show that plasmid mutation rates scale logarithmically with copy number and that the supply of new mutations consistently surpasses the impact of segregational drift across all copy numbers. These results underscore plasmids as powerful drivers of bacterial evolvability, where they can potentiate the evolution of critical traits such as antibiotic resistance.

Why do you highlight this publication?

This work explains a trade-off in systems with many DNA copies, such as antimicrobial resistance plasmids: more copies create more opportunities for new mutations, but random inheritance makes any mutation more likely to be lost. Using theory, computational simulations, bioinformatic analysis and experimental validation, we show that the overall plasmid mutation rate increases with copy number, but with diminishing returns. The key result is that the extra supply of new mutations outweighs the losses from random inheritance, making multicopy DNA elements strong engines of evolutionary change, and helping explain how plasmid-borne antibiotic resistance can emerge and optimize rapidly.