
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.24.609537
preprint
1
Article
Switch-like Gene Expression Modulates Disease Susceptibility
Aqil Alber
Li Yanyan
Wang Zhiliang
Islam Saiful
Russell Madison
Kunovac Kallak Theodora
Saitou Marie
Gokcumen Omer http://orcid.org/0000-0003-4371-679X

Masuda Naoki http://orcid.org/0000-0003-1567-801X

25 8 2024
2024.08.24.609537https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.24.609537
nihpp-2024.08.24.609537.pdf
Abstract

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five (∼18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p <10 -4 ) and vaginal atrophy (44-fold, p <10 -4 ), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12 . We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.
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pmc
