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Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements

Authors: David Angeles-Albores, Carmie Puckett-Robinson, Brian A. Williams, Barbara Wold and Paul W. Sternberg

Abstract

RNA-seq is commonly used to identify genetic modules that respond to perturbations. In single cells, transcriptomes have been used as phenotypes, but this concept has not been applied to whole-organism RNA-seq. Also, quantifying and interpreting epistatic effects using expression profiles remains a challenge. We developed a single coefficient to quantify transcriptome-wide epistasis that reflects the underlying interactions and which can be interpreted intuitively. To demonstrate our approach, we sequenced four single and two double mutants of Caenorhabditis elegans. From these mutants, we reconstructed the known hypoxia pathway. In addition, we uncovered a class of 56 genes with hif-1-dependent expression which have opposite changes in expression in mutants of two genes which cooperate to negatively regulate HIF-1 abundance; however, the double mutant of these genes exhibits suppression epistasis. This class violates the classical model of HIF-1 regulation, but can be explained by postulating a role of hydroxylated HIF-1 in transcriptional control.

File Structure

mprsq
│   README.md
│   kallisto_commands_sh    
│
└───input -- input files used for this project. Note: due to their size, HD5
             files are gitignored, but can be found at the GEO.
└───experimental_docs - experimental documents for this project
└───sleuth_all_adjusted - contains R code for sleuth processing
└───src - contains all Jupyter notebooks with python analysis
└───output
      └─── supplementary_tables/ -- contains CSV files containing quantified results
      └─── rank_plots/ -- pairwise rank plots for all pairwise combinations
      └─── other_figs -- all other figures generated for this project
└───docs - website

Contact

pws@caltech.edu

Technical assistance

dangeles@caltech.edu

Acknowledgements

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