Causal Variation in Yeast Sporulation Tends to Reside in a Pathway Bottleneck

Abstract

There has been extensive debate over whether certain classes of genes are more likely than others to contain the causal variants responsible for phenotypic differences in complex traits between individuals. One hypothesis states that input/output genes positioned in signal transduction bottlenecks are more likely than other genes to contain causal natural variation. The IME1 gene resides at such a signaling bottleneck in the yeast sporulation pathway, suggesting that it may be more likely to contain causal variation than other genes in the sporulation pathway. Through crosses between natural isolates of yeast, we demonstrate that the specific causal nucleotides responsible for differences in sporulation efficiencies reside not only in IME1 but also in the genes that surround IME1 in the signaling pathway, including RME1, RSF1, RIM15, and RIM101. Our results support the hypothesis that genes at the critical decision making points in signaling cascades will be enriched for causal variants responsible for phenotypic differences.

Author Summary

Distinguishing the small number of genetic variants that impact phenotypes from the huge number of innocuous variants within an individual's genome is a difficult problem. Several hypotheses concerning the location of causal variants have been put forward based on the fact that genes are often organized into signaling cascades where the activation of a gene at the top of a pathway in turn activates large numbers of downstream genes. One hypothesis states that causal variations are more likely to reside in the genes at the top of these pathways because their effects are amplified by the signaling cascade. Here we provide support for this hypothesis by showing that causal genetic variants in yeast sporulation cluster around a gene at the top of the sporulation signaling cascade. Our result suggests a way to focus the search for causal genetic variants, including those that cause disease, on a smaller number of genes that are more likely to harbor important variations.