Biology subjects

Hodgins-Davis, A.

Publications and source records attributed to Hodgins-Davis, A..

4 recordsLinked to original sources

bioRxiv2022

Human commensal Candida albicans strains demonstrate substantial within-host diversity and retained pathogenic potential

Candida albicans is a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen. C. albicans is remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we undertook an examination of commensal isolates from healthy donors with a goal of identifying site-specific phenotypic adaptation and genetic variation associated with these phenotypes. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverse C. albicans strains, and that this genetic diversity includes both SNVs and structural rearrangements. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterized ZMS1 transcription factor that was sufficient to drive hyper invasion into agar. However, our commensal strains retained the capacity to cause disease in systemic models of infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity of C. albicans and suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.

microbiology↗

bioRxiv2019

Empirical measures of mutational effects define neutral models of regulatory evolution in Saccharomyces cerevisiae

Understanding how phenotypes evolve requires disentangling the effects of mutation generating new variation from the effects of selection filtering it. Evolutionary models frequently assume that mutation introduces phenotypic variation symmetrically around the population mean, yet few studies have tested this assumption by deeply sampling the distributions of mutational effects for particular traits. Here, we examine distributions of mutational effects for gene expression in the budding yeast Saccharomyces cerevisiae by measuring the effects of thousands of point mutations introduced randomly throughout the genome. We find that the distributions of mutational effects differ for the 10 genes surveyed and violate the assumption of normality. For example, all ten distributions of mutational effects included more mutations with large effects than expected for normally distributed phenotypes. In addition, some genes also showed asymmetries in their distribution of mutational effects, with new mutations more likely to increase than decrease the genes expression or vice versa. Neutral models of regulatory evolution that take these empirically determined distributions into account suggest that neutral processes may explain more expression variation within natural populations than currently appreciated. Significance statementNew mutations tend to arise randomly throughout the genome, but their phenotypic effects are often not random. This disconnect results from interactions among genes that define the genotype-phenotype map. The structure of this map is poorly known and different for each trait, making it challenging to predict the distribution of mutational effects for specific phenotypes. Empirical measures of the distribution of mutational effects are thus necessary to understand how traits can change in the absence of natural selection. In this work, we define such distributions for expression of ten genes in S. cerevisiae and show that they predict greater neutral expression divergence than commonly used models of phenotypic evolution.

evolutionary biology↗

bioRxiv2018

Fitness effects of altering gene expression noise in Saccharomyces cerevisiae

Gene expression noise is an evolvable property of biological systems that describes differences in gene expression among genetically identical cells in the same environment. Prior work has shown that expression noise is heritable and can be shaped by natural selection, but the impact of variation in expression noise on organismal fitness has proven difficult to measure. Here, we quantify the fitness effects of altering expression noise for the TDH3 gene in Saccharomyces cerevisiae. We show that increases in expression noise can be deleterious or beneficial depending on the difference between the average expression level of a genotype and the expression level maximizing fitness. We also show that a simple model relating single-cell expression levels to population growth produces patterns that are consistent with our empirical data. We use this model to explore a broad range of average expression levels and expression noise, providing additional insight into the fitness effects of variation in expression noise.

evolutionary biology↗

bioRxiv2017

Effects of mutation and selection on plasticity of TDH3 promoter activity in Saccharomyces cerevisiae

Phenotypic plasticity is an evolvable property of biological systems that can arise from environment-specific regulation of gene expression. To better understand the evolutionary and molecular mechanisms that give rise to plasticity in gene expression, we quantified the effects of 235 single nucleotide mutations in the Saccharomyces cerevisiae TDH3 promoter (PTDH3) on the activity of this promoter in media containing glucose, galactose, or glycerol as a carbon source. We found that the distributions of mutational effects differed among environments because many mutations altered the plastic response exhibited by the wild type allele. Comparing the effects of these mutations to the effects of 30 PTDH3 polymorphisms on expression plasticity in the same environments provided evidence of natural selection acting to prevent the plastic response in PTDH3 activity between glucose and galactose from becoming larger. The largest changes in expression plasticity were observed between fermentable (glucose or galactose) and nonfermentable (glycerol) carbon sources and were caused by mutations located in the RAP1 and GCR1 transcription factor binding sites. Mutations altered expression plasticity most frequently between the two fermentable environments, however, with mutations causing significant changes in plasticity between glucose and galactose distributed throughout the promoter, suggesting they might affect chromatin structure. Taken together, these results provide insight into the molecular mechanisms underlying gene-by-environment interactions affecting gene expression as well as the evolutionary dynamics affecting natural variation in plasticity of gene expression.\n\nSignificance StatementFrom seasonal variation in the color of butterfly wings to trees bending toward the light, organisms often change in response to their environment. These changes, known as phenotypic plasticity, can result from differences in how genes are expressed among environments. Mutations causing environment-specific changes in gene expression provide raw material for phenotypic plasticity, but their frequency, effect size and direction of effects among environments are not well understood. This study shows that mutations in the promoter of a yeast metabolic gene often display environment-dependent effects on gene expression and that these environment-dependent effects have been shaped by selection in natural populations.

genetics↗