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.
Highlights
Understanding the genetic architecture of complex traits is a major challenge in quantitative genetics
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
Chosen to have the most extreme phenotypic differences, and it is possible that natural variation in strains with more moderate phenotypes resides in genes outside of the sporulation bottleneck
Summary
Understanding the genetic architecture of complex traits is a major challenge in quantitative genetics. Whether causal variants share characteristics is a topic of great debate in the quantitative genetics community These characteristics include whether variants are located in coding or non-coding genomic regions [1,2], in specific hotspot genes or spread throughout the genome [3,4], and whether certain classes of genes are more likely to harbor hotspots than others [5,6,7]. Input/output genes ‘‘integrate an extensive array of inputs, the regulatory state, and they produce an on or off transcriptional output’’ whose expression drives differentiation of a specific cell fate [3] This gives the signaling pathway a characteristic hourglass shape. Input/output genes are positioned centrally and as such are hypothesized to be likely locations for the accumulation of causal variation, as their variants should provide strong, but specific effects on the traits they regulate
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