Biology subjects

Kusmartsev, V.

Publications and source records attributed to Kusmartsev, V..

2 recordsLinked to original sources

bioRxiv2020

Tunable phenotypic variability through an autoregulatory alternative sigma factor circuit

Genetically identical individuals in bacterial populations can display significant phenotypic variability. This variability can be functional, for example by allowing a fraction of stress prepared cells to survive an otherwise lethal stress. The optimal fraction of stress prepared cells depends on environmental conditions. However, how bacterial populations modulate their level of phenotypic variability remains unclear. Here we show that the alternative sigma factor σV circuit in B. subtilis generates functional phenotypic variability that can be tuned by stress level, environmental history, and genetic perturbations. Using single-cell time-lapse microscopy and microfluidics, we find the fraction of cells that immediately activate σV under lysozyme stress depends on stress level and on a memory of previous stress. Iteration between model and experiment reveals that this tunability can be explained by the autoregulatory feedback structure of the sigV operon. As predicted by the model, genetic perturbations to the operon also modulate the response variability. The conserved sigma-anti-sigma autoregulation motif is thus a simple mechanism for bacterial populations to modulate their heterogeneity based on their environment.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2019

Cytosine methylation affects the mutability of neighbouring nucleotides in human, Arabidopsis, and rice

Methylated cytosines deaminate at higher rates than unmethylated cytosines and the lesions they produce are repaired less efficiently. As a result, methylated cytosines are mutational hotspots. Here, combining rare polymorphism and base-resolution methylation data in humans, Arabidopsis thaliana, and rice (Oryza sativa), we present evidence that methylation state affects mutation dynamics not only at the focal cytosine but also at neighbouring nucleotides. In humans, contrary to prior suggestions, we find that nucleotides in the close vicinity ({+/-}3nt) of methylated cytosines mutate less frequently. In contrast, methylation is associated with increased neighbourhood mutation risk in A. thaliana and rice. The difference in mutation risk associated with methylation is less pronounced further away from the focal CpG, is modulated by regional GC content, and enhanced in heterochromatic regions. Our results are consistent with a model where elevated risk at neighbouring bases is linked to lesion formation at the focal cytosine and subsequent long-patch repair. Our results provide evidence that cytosine methylation has a broader mutational footprints than commonly assumed. They also illustrate that methylation is not intrinsically associated with higher mutation risk for surrounding bases, but that mutagenic effects reflect evolved species-specific and lesion-specific predispositions to elicit error-prone long-patch DNA repair.

genomics↗