Modeling Chromosome Maintenance as a Property of Cell Cycle in Saccharomyces cerevisiae

Defects in DNA repair, synthesis, and chromosome transmission can often cause chromosome instability, which are understood with respect to molecular-genetic mechanisms. However, transition from descriptive models to quantitative ones is generally difficult. Here we use a computationally intensive numerical technique based on linear programming to analyze the processes of chromosome maintenance during the cell cycle in yeast, Saccharomyces cerevisiae. We first experimentally identify 19 genes that when ectopically expressed cause chromosome instability. We then build an 18 x 19 matrix by assaying the genetic interactions of pairs of genes that each normally functions to maintain chromosomes, including the 19 genes discovered here. We then use a \"seriation\" algorithm based on linear optimization to find an optimal arrangement of rows and columns to confirm an optimum temporal arrangement of gene influence during cell cycle phases. We experimentally demonstrate that the method yields new biological insights, which we test and validate.