Global Linkage Map Connects Meiotic Centromere Function to Chromosome Size in Budding Yeast

Abstract

Abstract Synthetic genetic array (SGA) analysis automates yeast genetics, enabling high-throughput construction of ordered arrays of double mutants. Quantitative colony sizes derived from SGA analysis can be used to measure cellular fitness and score for genetic interactions, such as synthetic lethality. Here we show that SGA colony sizes also can be used to obtain global maps of meiotic recombination because recombination frequency affects double-mutant formation for gene pairs located on the same chromosome and therefore influences the size of the resultant double-mutant colony. We obtained quantitative colony size data for ~1.2 million double mutants located on the same chromosome and constructed a genome-scale genetic linkage map at ~5 kb resolution. We found that our linkage map is reproducible and consistent with previous global studies of meiotic recombination. In particular, we confirmed that the total number of crossovers per chromosome tends to follow a simple linear model that depends on chromosome size. In addition, we observed a previously unappreciated relationship between the size of linkage regions surrounding each centromere and chromosome size, suggesting that crossovers tend to occur farther away from the centromere on larger chromosomes. The pericentric regions of larger chromosomes also appeared to load larger clusters of meiotic cohesin Rec8, and acquire fewer Spo11-catalyzed DNA double-strand breaks. Given that crossovers too near or too far from centromeres are detrimental to homolog disjunction and increase the incidence of aneuploidy, our data suggest that chromosome size may have a direct role in regulating the fidelity of chromosome segregation during meiosis.