Open AccessA rapidly reversible mutation generates subclonal genetic diversity and unstable drug resistance
Author(s) -
Lufeng Dan,
Yuze Li,
Shuhua Chen,
Jingbo Liu,
Yu Wang,
Fangting Li,
Xiangwei He,
Lucas B. Carey
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2019060118
Subject(s) - biology , genetics , reversion , mutation , mutation rate , genome , population , whole genome sequencing , coding region , mutation accumulation , gene duplication , drug resistance , gene , phenotype , demography , sociology
Significance Mutations that confer drug resistance often confer a growth defect in the absence of drug. Mechanisms that enable temporary mutations—mutations that provide drug resistance but frequently revert back to the wild-type genomic DNA sequence—would therefore be advantageous for organisms forced to adapt in changing environments. Here, we show that rapidly reversible mutations are frequently generated by microhomology-mediated tandem duplications (MTDs) in the gene ssp1, causing rapamycin resistance and a growth defect, and reversal back to wild type restores fitness and drug sensitivity. We also found that genomes have evolved to minimize the number of potentially deleterious MTDs and used machine learning to determine the sequence-encoded rules that govern the formation and collapse of MTDs.