Abstract
Expression profiling holds great promise for genetics because of its ability to measure thou-sands of genes quantitatively in parallel. Although transcriptomes have recently been used to perform epistasis analyses for pathway reconstruction, there has not been a systematic effort to understand how expression profiles will vary among various mutants of the same gene. Here, we study an allelic series in C. elegans consisting of one wild type and two mutant alleles of mdt-12, a highly pleiotropic gene whose gene product is a subunit of Mediator complex, which is essential for transcriptional initiation in eukaryotes. We developed a false hit analysis to identify which populations of genes commonly differentially expressed with respect to the wild type are likely the result of statistical artifact. We concluded that expression perturbations caused by these alleles split into four distinct modules called phenotypic classes. To understand the dominance relationship between the two mutant alleles, we developed a dominance analysis for transcriptional data. Dominance analysis of these phenotypic classes support a model where mdt-12 has multiple functional units that function independently to target the Mediator complex to specific genetic loci.
Author Summary Expression profiling is a way to quickly and quantitatively measure the expression level of every gene in an organism. As a result, these profiles could be used as phenotypes with which to perform genetic analyses (i.e., to figure out what genes interact with each other) as well as to dissect the molecular properties of each gene. Before we can perform these analyses, we have to figure out the rules that apply to these measurements. In this paper, we develop new concepts and methods with which to study an allelic series. Briefly, allelic series are an important aspect of genetics because different alleles encode different versions of a gene. By studying these different versions, we can make statements about how function is encoded within the sequence of a gene. We apply our methods to the mdt-12 gene, which encodes a subunit of the Mediator complex. Though we know it is essential for all transcriptional activity in eukaryotes, we understand very little about how the Mediator complex functions to generate both general and specific phenotypes. The reason for this is the genes that encode these subunits are associated with general sickness and multiple phenotypes when mutated, which makes them challenging to study genetically. We show that transcriptomic phenotypes renders the study of general factors such as mdt-12 feasible.
Supplementary Data The website for the Supplementary Data for this project is still under construction and will be available shortly. All code, data and figures are available upon request.