Genotype-by-environment interactions govern fitness changes associated with adaptive mutations in two-component response systems.

Introduction: Two-component response systems (TCRS) are the main mechanism by which prokaryotes acclimate to changing environments. These systems are composed of a membrane bound histidine kinase (HK) that senses external signals and a response regulator (RR) that activates transcription of response genes. Despite their known role in acclimation, little is known about the role TCRS play in environmental adaptation. Several experimental evolution studies have shown the acquisition of mutations in TCRS during adaptation, therefore here we set out to characterize the adaptive mechanism resulting from these mutations and evaluate whether single nucleotide changes in one gene could induce variable genotype-by-environment (GxE) interactions. Methods: To do this, we assessed fitness changes and differential gene expression for four adaptive mutations in cusS, the gene that encodes the HK CusS, acquired by Escherichia coli during silver adaptation. Results: Fitness assays showed that as the environment changed, each mutant displayed a unique fitness profile with greatest fitness in the original selection environment. RNAseq then indicated that, in ± silver nitrate, each mutant induces a primary response that upregulates cusS, its RR cusR, and constitutively expresses the target response genes cusCFBA. This then induces a secondary response via differential expression of genes regulated by the CusR through TCRS crosstalk. Finally, each mutant undergoes fitness tuning through unique tertiary responses that result in gene expression patterns specific for the genotype, the environment and optimized for the original selection conditions. Discussion: This three-step response shows that different mutations in a single gene leads to individualized phenotypes governed by unique GxE interactions that not only contribute to transcriptional divergence but also to phenotypic plasticity.

Characterization of the 2016-2017 Dermatology Standardized Letter of Recommendation.

Objective: We aimed to analyze the reformatted standard letter of recommendation (SLOR) for dermatology residents to examine trends in grading and content based on the positions of the letter writers, their backgrounds, and their relationship with the applicant, as well as to evaluate the SLOR's ability to discriminate applicants. Design: This was a retrospective characterization study of dermatology SLORs from the 2016-17 application cycle. Setting: We examined SLORs received by The Ohio State University, the University of Oklahoma, and Hofstra University Northwell Health dermatology residency programs. Participants: We included dermatology residency applicants and their letter writers from the 2016-17 application cycle. Results: A total of 141 SLORs were analyzed from 115 applicants. SLORs demonstrated grade inflation from letter writers of all backgrounds. Ratings for research potential and inquisitive nature were significantly lower than ratings for other categories. Letter writers with limited clinical and research contact graded applicants significantly lower than did writers who had more extensive contact. Word boxes were underutilized. Conclusion: The dermatology SLOR is useful in differentiating applicants, and ratings correlate with the relationships that letter writers have with their applicants. Residency programs should be aware of these findings when evaluating letters of recommendation for applicants.