Open Access Te Herenga Waka-Victoria University of Wellington
3 files

Phenotypic implications of genetic interaction networks in Saccharomyces cerevisiae

posted on 2022-07-28, 04:35 authored by Busby, Bede Phillip

Gene functions were studied as extensive networks comprising synergistic functional interactions between overlapping pairs of genes. Elucidation of such networks related to drug phenotypes (statins in this thesis) provides additional information to classical genetics as to what genes and metabolic pathways might be involved in phenotypes and, importantly, where side-effects might arise in drug effects.

A key question is whether there are genetic interaction networks that vary with individuals and with phenotypes. To answer this question a panel of twenty-six fully sequenced yeast strains from the Saccharomyces Genome Resequencing Project (SGRP; Sanger Institute) was screened for statin resistance to approximate a model for individuals in a human population. Three strains (Y55, SK1 and YPS606) were shown to be 500% more resistant to atorvastatin than the S288C laboratory control strain and were selected for further analysis.

Synthetic genetic array analysis (SGA) and chemical genetic profiling were utilised to elucidate genetic interaction networks in the four different strains. SGA analysis depends on the availability of a genome-wide deletion mutant array (DMA) which already exists for S288C and the current studies constructed equivalent Y55-, SK1-, and YS606-strain specific deletion mutant arrays called here “ssDMA’s”. Creating the new ssDMAs involved six back-crossings (1-1/2⁶) of Y55, SK1 and YPS606 with S288C to place the genome-wide deletion mutations of S288C on the genetic background of the strains using appropriate selection markers between each backcrossing. The four DMAs were then subjected to chemical genetic profiling with two statin drugs and also subjected to SGA analysis utilising five query genes chosen for their involvement with the cellular response to statins. The query genes HMG1, HMG2, ARV1, BTS1 and OPI3 were constructed to be strain specific and generated a total 25 genetic interaction networks. The chemical genetic profiles in the ssDMAs identified off-target interactions genes associated with the resistance phenotype in Y55, SK1, and YPS606 that were not observed to show genetic interactions in the more sensitive S288c strain. There was little conservation of the genetic interaction networks elicited by the specific query genes between the strains with the exception of OPI3. There was, however, conservation of fundamental cellular processes, as might be expected, but the genes encoding these processes in the SGAs of the different strains were for the most part different. Therefore, we conclude that the genetic interaction networks concerning statins are different between individuals.


Copyright Date


Date of Award



Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Cell and Molecular Bioscience

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level


Degree Name

Doctor of Philosophy

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Socio-Economic Outcome code

970106 Expanding Knowledge in the Biological Sciences

ANZSRC Type Of Activity code


Victoria University of Wellington Item Type

Awarded Doctoral Thesis



Victoria University of Wellington School

School of Biological Sciences


Atkinson, Paul; Teesdale-Spittle, Paul