PhD Seminar: Thuy Nguyen
Public Seminar for Thuy Nguyen
Supervisor: Dr. Brenda Andrews
Title: Exploring Complex Haploinsufficiency
Location: Donnelly Centre, Red Room
Date and Time: April 2nd, 2024 at 10:00 AM
Abstract: Many genetic and epigenetic phenomena are thought to underlie missing heritability including interactions between genes in a functional network. An interaction between two genes is defined by an observed phenotype with characteristics not explainable by the additive effects of mutating both genes. CHI, also referred to as nonallelic/biallelic/unlinked non-complementation in classical genetics, is the phenomenon in which mutant alleles from two different genes fail to complement a phenotype when heterozygous at both loci. I utilized the model organism S. cerevisiae and automated genetics to query for CHI in the context of budding yeast’s set of highly conserved essential genes. First, I assessed growth phenotypes associated with monogenic heterozygosity in different environmental conditions, establishing a catalogue of heterozygous single-mutant fitness phenotypes. Then, I used a library of Temperature Sensitive (TS) mutants of essential yeast genes to generate a collection of functionally hemizygous diploids, which I screened for potential CHI interactions. I also performed further analysis of the fitness of a selected set of double heterozygous mutants and the corresponding single heterozygous mutants to better understand the CHI space in yeast. To complement these datasets, I also performed screens to compare the different effects on fitness conferred by deletion mutations and hypomorphic alleles of essential genes in diverse conditions. My experiments found that deletion mutants and hypomorphic temperature sensitive mutants behave differently as heterozygotes, and that CHI pairs occur between different genes than GI found in haploids and are far rarer but still having generalizable trends. The result of this work contributes to our understanding of missing heritability and provides a clearer view of the functional wiring of the eukaryotic genome.