Comparative Analysis of Human Tissue Interactomes Reveals Factors Leading to Tissue-Specific Manifestation of Hereditary Diseases

Abstract

An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.

HIPPIE v2.0: enhancing meaningfulness and reliability of protein–protein interaction networks

“…In particular, we showed that when cellular signaling is studied in an infectious or genetic disease context, combining both gene expression information from the tissue affected by the disease and predicted network information flow, serves to highlight important mediators of disease from the PPI hairball surrounding the studied proteins (29). Indeed, disease-causing proteins tend to form an increased number of tissue-specific PPIs in the tissues that they affect (38). …”

A Differentiation Transcription Factor Establishes Muscle-Specific Proteostasis in Caenorhabditis elegans

“…Although the expression of many disease-associated proteins is not tissue-specific, many protein misfolding diseases exhibit tissue-specific vulnerability [71, 72]. For example, mutations in the ubiquitously expressed co-chaperone DNAJB6 cause a tissue-specific disease, limb-girdle muscular dystropy [18].…”

The TissueNet v.2 database: A quantitative view of protein-protein interactions across human tissues

“…(9,12,13)). The value of the resulting tissue-sensitive interaction networks (interactomes) was demonstrated in several applications, where tissue interactomes were shown to outperform the global, unfiltered interactome, in prioritizing disease genes (12–16) or to illuminate the molecular basis of tissue-selective hereditary diseases (17). …”

“…As we previously showed, this comparison is key in studying the tissue-specific effects of disease proteins (17). TissueNet v.2 is an enhanced version of TissueNet that includes significant data expansion, increased usability, and provides a new quantitative view of the query protein and its tissue-associated interactions.…”