Author ORCID Identifier:

https://orcid.org/0000-0002-8817-574X

Date of Graduation

12-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

Lewis, Jeffrey

Committee Member

Westerman, Erica

Second Committee Member

Pinto, Ines

Third Committee Member

Harris, Leonard

Fourth Committee Member

Zhang, Qingyang

Keywords

CRISPR screens; Gene-by-environment interactions; High Osmolarity Glycerol (HOG) Pathway; Stress resilience; Transcriptomics; Wild yeast

Abstract

Survival in fluctuating environments demands that organisms effectively anticipate and respond to future challenges. This capacity is shaped by both genetic background and environmental context. In this dissertation, I apply a population aware lens to explore how genetic diversity and environmental conditions intersect to shape stress survival. Integrating functional genomics and transcriptomics in Saccharomyces cerevisiae (brewer’s yeast) and a vertebrate (common canary) system, I dissect gene-by-environment (GE) interactions that underpin resilience. First, I move beyond a single reference genome by using a pan-genomic CRISPR knockout screen to assess osmotic stress survival across diverse S. cerevisiae isolates. This analysis reveals a small, conserved core of stress-defense genes. More interestingly, I also identify extensive strain-specific fitness effects. These include opposite phenotypic effects of key regulators and contributions from genes absent from the laboratory reference genome, demonstrating the importance of interrogating the accessory genome. Second, I investigate the plasticity of the High Osmolarity Glycerol (HOG) MAPK signaling pathway. Comparative transcriptomics reveal that Hog1’s role extends beyond osmoadaptation to other stresses, but its activation dynamics and downstream targets are highly strain dependent. By mapping transcriptomic changes during mild stress, I identify the HOG pathway’s specific contributions to acquired resistance. In doing so, I show how an evolutionarily conserved pathway varies dramatically in its sensitivity and regulatory scope at the population level. Finally, I test the generality of these principles in a vertebrate host-pathogen model system. In this study, I explore the transcriptomic changes associated with diet-based modulation of host tolerance (the ability to reduce pathology at a given pathogen load). Biological Processes identified as differentially expressed share translational machinery. This intracellular driver of environmental influence on survival reflects the same resource allocation trade-offs observed in yeast, suggesting a conserved principle for managing environmental challenges. Together, these studies demonstrate that while core stress-response architectures are conserved, their functional deployment and ultimate effects on survival are highly dependent on the genomic and environmental landscape. In sum, these findings provide a novel perspective for advancing stress biology by highlighting the functional role of the accessory genome, genetic and environmental drivers of survival.

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