In the age of genomics, an enormous challenge to the field is predicting phenotypes from genotypes. We combine classical genetics and molecular biology with bioinformatics approaches such as genomics, transcriptomics and proteomics to assess how organisms respond to constantly changing environmental stresses. Yeast have evolved biochemical pathways including multiple drug resistance (MDR) to tolerate a broad class of toxic chemicals. However, there is considerable variation in growth inhibition across genetically distinct yeast strains in response to different chemicals. This leads to our guiding question: across genetically distinct individuals, what kind of genetic variation matters the most in predicting phenotypes?
Variation across genomes is expected but variation in key proteins are potent modulators of genetic diversity in response to environmental stresses. Transcription factors have more notable impact on phenotypes since they can regulate multiple genes thus have multiple and/or cumulative effects. These proteins are called master variators. To uncover master variators we have several ongoing projects.
Using genome-wide analysis studies we have uncovered variation in Yrr1, a transcription factor that redirects cellular pathways in response to DNA damaging drug 4NQO (4-nitroquinoline 1-oxide). We have focused on potential hypervariable phosphorylation sites that regulate the function of Yrr1 in yeast.
We have used transcriptomic analysis to predict the effect of 4MCHM, a chemical spilled in Elk River in January 2014, on yeast. This understudied chemical affects several pathways and we have uncovered treatments that alleviate growth inhibition by this chemical. We are also addressing the possible effect on development in a model organism Xenopus.
We have used comparative phenotypic analysis of Roundup resistant yeast to propose the existence of alternative metabolic pathways resistant to chemical inhibition. Roundup is an herbicide widely used in agriculture targets aromatic amino acid biosynthesis. Roundup resistance is a recent trait and future research will explore how yeast adapt and if the trait can spread through wild populations.
To understand how copper nanoparticles affect microbes we are mapping regions of the genome that regulate response to toxic levels of copper. Copper is a micronutrient that is both essential and highly toxic to humans. Dysregulation of copper levels is important in progression of several neurological diseases.
In each case we have utilized the different methods to address the underlying genetic cause of phenotypic variation in model organisms.