The Fitness Consequences of Aneuploidy Are Driven by Condition-Dependent Gene Effects

Abstract

Aneuploidy is a hallmark of tumor cells, and yet the precise relationship between aneuploidy and a cell’s proliferative ability, or cellular fitness, has remained elusive. In this study, we have combined a detailed analysis of aneuploid clones isolated from laboratory-evolved populations of Saccharomyces cerevisiae with a systematic, genome-wide screen for the fitness effects of telomeric amplifications to address the relationship between aneuploidy and cellular fitness. We found that aneuploid clones rise to high population frequencies in nutrient-limited evolution experiments and show increased fitness relative to wild type. Direct competition experiments confirmed that three out of four aneuploid events isolated from evolved populations were themselves sufficient to improve fitness. To expand the scope beyond this small number of exemplars, we created a genome-wide collection of >1,800 diploid yeast strains, each containing a different telomeric amplicon (Tamp), ranging in size from 0.4 to 1,000 kb. Using pooled competition experiments in nutrient-limited chemostats followed by high-throughput sequencing of strain-identifying barcodes, we determined the fitness effects of these >1,800 Tamps under three different conditions. Our data revealed that the fitness landscape explored by telomeric amplifications is much broader than that explored by single-gene amplifications. As also observed in the evolved clones, we found the fitness effects of most Tamps to be condition specific, with a minority showing common effects in all three conditions. By integrating our data with previous work that examined the fitness effects of single-gene amplifications genome-wide, we found that a small number of genes within each Tamp are centrally responsible for each Tamp’s fitness effects. Our genome-wide Tamp screen confirmed that telomeric amplifications identified in laboratory-evolved populations generally increased fitness. Our results show that Tamps are mutations that produce large, typically condition-dependent changes in fitness that are important drivers of increased fitness in asexually evolving populations.

Heterozygote Advantage Is a Common Outcome of Adaptation inSaccharomyces cerevisiae

“…The same region was previously found expanded in an evolved strain (E8) in glucose-limited chemostats (Paquin and Adams 1983;Dunham et al 2002). Also, among the clones with high fitness in glucose-limited chemostats screened by (Sunshine et al 2015) were those with a partial amplification of the right arm of chromosome IV. The HXT6/7 CNV is an approximately 10-fold expansion of the region including the high-affinity glucose transporters HXT6 and HXT7.…”

“…In the chrXV CNV, 300 of the haploidized genes and 60 of the duplicated ones were also found haploidized and duplicated, respectively, in a clone (E7) previously evolved in glucose-limited chemostats (Paquin and Adams 1983;Dunham et al 2002). Also, clones where the distal end of the left arm of chromosome XV was amplified had an increased fitness in glucose-limited chemostats (Sunshine et al 2015).…”

“…It appears that this mutation is pleiotropic in fitness, being adaptive in low glucose but maladaptive in an environment rich in glucose. Such fitness trade-offs are common in yeast (Lang et al 2009;Wenger et al 2011;Sunshine et al 2015). If we consider ploidy as an environment of an allele, as it contributes to the phenotype developed, then our expectation of heterozygote advantage in adapting diploids leads to an expectation of adaptive mutations often being also pleiotropic in the fitness space across environments.…”

“…Partitioning the relative contribution of individual genes among the hundreds in each large CNV is not straightforward. For the chrIV CNV and the duplicated region of the chrXV CNV, one could possibly measure the fitness of a series of partially overlapping CNVs with the telomeric amplicon approach used by Sunshine et al (2015) and assume that individual gene fitness effects are independent and additive. A complementary approach would be to measure the competitive fitness of single-gene knockdowns of the haploidized genes in the chrXV CNV (e.g., STD1).…”

“…In the chrXV CNV, 300 of the haploidized genes and 60 of the duplicated ones were also found haploidized and duplicated, respectively, in a clone (E7) previously evolved in glucose-limited chemostats (Paquin and Adams 1983;Dunham et al 2002). Also, clones where the distal end of the left arm of chromosome XV was amplified had an increased fitness in glucose-limited chemostats (Sunshine et al 2015).The chrIV CNV is a transposon-mediated partial duplication of chromosome IV including 334 genes, among which are 63 that are essential (Deutschbauer et al 2005), and 3 that Heterozygote Advantage in Adapting Diploids 1407 are deleterious when overexpressed (Tomala and Korona 2013). Also, among the duplicated genes are the negative regulator of glucose transport MTH1 and the glucose transporters HXT3, HXT6, and HXT7 (Table 2).…”