The differential activity of biological processes in tissues and cell subsets can illuminate disease-related processes and cell-type identities

Motivation: The distinct functionalities of human tissues and cell types underlie complex phenotype-genotype relationships, yet often remain elusive. Harnessing the multitude of bulk and single-cell human transcriptomes while focusing on processes can help reveal these distinct functionalities. Results: The Tissue-Process Activity (TiPA) method aims to identify processes that are preferentially active or underexpressed in specific contexts, by comparing the expression levels of process genes between contexts. We tested TiPA on 1579 tissue-specific processes and bulk tissue transcriptomes, finding that it performed better than another method. Next, we used TiPA to ask whether the activity of certain processes could underlie the tissue-specific manifestation of 1233 hereditary diseases. We found that 21% of the disease-causing genes indeed participated in such processes, thereby illuminating their genotype-phenotype relationships. Lastly, we applied TiPA to single-cell transcriptomes of 108 human cell types, revealing that process activities often match cell-type identities and can thus aid annotation efforts. Hence, differential activity of processes can highlight the distinct functionality of tissues and cells in a robust and meaningful manner.

Automated summary

The study introduces a method called Tissue-Process Activity (TiPA), which identifies preferentially active or underexpressed processes in specific contexts by comparing the expression levels of process genes between contexts. The results show that TiPA outperforms other methods and provides insights into the genotype-phenotype relationships of hereditary diseases and the functionality of cell types.