Response outcomes gate the impact of expectations on perceptual decisions

ABSTRACTPerceptual decisions are not only determined by current sensory information but are also influenced by expectations based on recent experiences. Can the impact of these expectations be flexibly modulated based on the outcome of previous decisions? We trained rats in several two-alternative forced choice auditory tasks, where the probability to repeat the previous stimulus category was varied in blocks of trials. All rats capitalized on the serial correlations of the stimulus sequence by consistently exploiting atransition bias:a tendency to repeat or alternate their previous response using an internal trial-by-trial estimate of the sequence repeating probability. Surprisingly, this bias was null in trials immediately following an error. The internal estimate however was not reset and it became effective again causing a bias after the next correct response. This ability to rapidly activate and inactivate the bias was captured by a non-linear generative model of rat behavior, whereby a reward-driven modulatory signal gated the use of the latent estimate of the environment statistics on the current decision. These results demonstrate that, based on the outcome of previous choices, rats flexibly modulate how expectations influence their current decisions.

Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis

Transition bias, an overabundance of transitions relative to transversions, has been widely reported among studies of mutations spreading under relaxed selection. However, demonstrating the role of transition bias in adaptive evolution remains challenging. We addressed this challenge by analyzing adaptive antibiotic-resistance mutations in the major human pathogen Mycobacterium tuberculosis. We found strong evidence for transition bias in two independently curated datasets comprising 152 and 208 antibiotic resistance mutations. This was true at the level of mutational paths (distinct, adaptive DNA sequence changes) and events (individual instances of the adaptive DNA sequence changes), and across different genes and gene promoters conferring resistance to a diversity of antibiotics. It was also true for mutations that do not code for amino acid changes (in gene promoters and the ribosmal gene rrs), and for mutations that are synonymous to each other and are therefore likely to have similar fitness effects, suggesting that transition bias can be caused by a bias in mutation supply. These results point to a central role for transition bias in determining which mutations drive adaptive antibiotic resistance evolution in a key pathogen.Significance statementWhether and how transition bias influences adaptive evolution remain open questions. We studied 296 DNA mutations that confer antibiotic resistance to the human pathogen Mycobacterium tuberculosis. We uncovered strong transition bias among these mutations and also among the number of times each mutation has evolved in different strains or geographic locations, demonstrating that transition bias can influence adaptive evolution. For a subset of mutations, we were able to rule out an alternative selection-based hypothesis for this bias, indicating that transition bias can be caused by a biased mutation supply. By revealing this bias among M. Tuberculosis resistance mutations, our findings improve our ability to predict the mutational pathways by which pathogens overcome treatment.

Whole-Genome Profiling of a Novel Mutagenesis Technique Using Proofreading-Deficient DNA Polymerase δ

A novel mutagenesis technique using error-prone DNA polymerase δ (polδ), the disparity mutagenesis model of evolution, has been successfully employed to generate novel microorganism strains with desired traits. However, little else is known about the spectra of mutagenic effects caused by disparity mutagenesis. We evaluated and compared the performance of the polδMKII mutator, which expresses the proofreading-deficient and low-fidelity polδ, in Saccharomyces cerevisiae haploid strain with that of the commonly used chemical mutagen ethyl methanesulfonate (EMS). This mutator strain possesses exogenous mutant polδ supplied from a plasmid, tthereby leaving the genomic one intact. We measured the mutation rate achieved by each mutagen and performed high-throughput next generation sequencing to analyze the genome-wide mutation spectra produced by the 2 mutagenesis methods. The mutation frequency of the mutator was approximately 7 times higher than that of EMS. Our analysis confirmed the strong G/C to A/T transition bias of EMS, whereas we found that the mutator mainly produces transversions, giving rise to more diverse amino acid substitution patterns. Our present study demonstrated that the polδMKII mutator is a useful and efficient method for rapid strain improvement based on in vivo mutagenesis.