{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:15:51Z","timestamp":1787498151157,"version":"build-2736575974"},"posted":{"date-parts":[[2024,8,26]]},"group-title":"Bioinformatics","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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 (\u223c18%) 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,\n                  <jats:italic>p<\/jats:italic>\n                  &lt;10\n                  <jats:sup>-4<\/jats:sup>\n                  ) and vaginal atrophy (44-fold,\n                  <jats:italic>p<\/jats:italic>\n                  &lt;10\n                  <jats:sup>-4<\/jats:sup>\n                  ), 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\n                  <jats:italic>ALOX12<\/jats:italic>\n                  . 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.\n                <\/jats:p>","DOI":"10.1101\/2024.08.24.609537","type":"posted-content","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T04:40:15Z","timestamp":1724647215000},"source":"Crossref","is-referenced-by-count":1,"title":["Switch-like Gene Expression Modulates Disease Susceptibility"],"prefix":"10.64898","author":[{"given":"Alber","family":"Aqil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiful","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Kunovac Kallak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Saitou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4371-679X","authenticated-orcid":false,"given":"Omer","family":"Gokcumen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-801X","authenticated-orcid":false,"given":"Naoki","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024082806250500000_2024.08.24.609537v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(61)80072-7"},{"key":"2024082806250500000_2024.08.24.609537v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(81)90413-X"},{"key":"2024082806250500000_2024.08.24.609537v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(83)90014-4"},{"key":"2024082806250500000_2024.08.24.609537v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/0168-9525(85)90088-5"},{"key":"2024082806250500000_2024.08.24.609537v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.51.5.786"},{"key":"2024082806250500000_2024.08.24.609537v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60678-8"},{"key":"2024082806250500000_2024.08.24.609537v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(88)90122-2"},{"key":"2024082806250500000_2024.08.24.609537v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063127"},{"key":"2024082806250500000_2024.08.24.609537v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature01763"},{"key":"2024082806250500000_2024.08.24.609537v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(03)00585-4"},{"key":"2024082806250500000_2024.08.24.609537v1.11","first-page":"880","article-title":"Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene","volume":"48","year":"1991","journal-title":"Am. J. Hum. Genet"},{"key":"2024082806250500000_2024.08.24.609537v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3849"},{"key":"2024082806250500000_2024.08.24.609537v1.13","first-page":"11","article-title":"Bimodal gene expression and biomarker discovery","volume":"9","year":"2010","journal-title":"Cancer Inform"},{"key":"2024082806250500000_2024.08.24.609537v1.14","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-11-S1-S8"},{"key":"2024082806250500000_2024.08.24.609537v1.15","doi-asserted-by":"crossref","first-page":"e20210109","DOI":"10.1590\/1678-4685-gmb-2021-0109","article-title":"An integrated approach to identify bimodal genes associated with prognosis in cancer","volume":"44","year":"2021","journal-title":"Genet. Mol. Biol"},{"key":"2024082806250500000_2024.08.24.609537v1.16","first-page":"100001","article-title":"Computational methods to identify bimodal gene expression and facilitate personalized treatment in cancer patients","volume":"100S","year":"2019","journal-title":"J. Biomed. Inform"},{"key":"2024082806250500000_2024.08.24.609537v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-98"},{"key":"2024082806250500000_2024.08.24.609537v1.18","doi-asserted-by":"publisher","DOI":"10.1214\/aos\/1176346577"},{"key":"2024082806250500000_2024.08.24.609537v1.19","doi-asserted-by":"publisher","DOI":"10.1021\/pr300864k"},{"key":"2024082806250500000_2024.08.24.609537v1.20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0214275"},{"key":"2024082806250500000_2024.08.24.609537v1.21","doi-asserted-by":"publisher","DOI":"10.2217\/fvl-2020-0188"},{"key":"2024082806250500000_2024.08.24.609537v1.22","doi-asserted-by":"crossref","first-page":"166291","DOI":"10.1016\/j.bbadis.2021.166291","article-title":"Sequence complementarity between human noncoding RNAs and SARS-CoV-2 genes: What are the implications for human health? Biochim","volume":"1868","year":"2022","journal-title":"Biophys. Acta Mol. Basis Dis"},{"key":"2024082806250500000_2024.08.24.609537v1.23","doi-asserted-by":"crossref","first-page":"147232","DOI":"10.1016\/j.gene.2023.147232","article-title":"Emerging role of microRNAs and long non-coding RNAs in COVID-19 with implications to therapeutics","volume":"861","year":"2023","journal-title":"Gene"},{"key":"2024082806250500000_2024.08.24.609537v1.24","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1038\/ncomms3260","article-title":"Genome-wide search for exonic variants affecting translational efficiency","volume":"4","year":"2013","journal-title":"Nat. Commun"},{"key":"2024082806250500000_2024.08.24.609537v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/5082"},{"key":"2024082806250500000_2024.08.24.609537v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242379"},{"key":"2024082806250500000_2024.08.24.609537v1.27","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-018-1451-z"},{"key":"2024082806250500000_2024.08.24.609537v1.28","doi-asserted-by":"publisher","DOI":"10.1210\/me.2014-1099"},{"key":"2024082806250500000_2024.08.24.609537v1.29","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2016.00183"},{"key":"2024082806250500000_2024.08.24.609537v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23809"},{"key":"2024082806250500000_2024.08.24.609537v1.31","first-page":"1121","article-title":"Sex differences in the HPA axis","volume":"4","year":"2014","journal-title":"Compr. Physiol"},{"key":"2024082806250500000_2024.08.24.609537v1.32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.cophys.2018.03.010","article-title":"The evolution of greater humoral immunity in females than males: implications for vaccine efficacy","volume":"6","year":"2018","journal-title":"Curr. Opin. Physiol"},{"key":"2024082806250500000_2024.08.24.609537v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2019.04.001"},{"key":"2024082806250500000_2024.08.24.609537v1.34","doi-asserted-by":"crossref","first-page":"665666","DOI":"10.3389\/fendo.2021.665666","article-title":"Comprehensive analysis of the expression and prognostic value of spint1\/2 in breast carcinoma","volume":"12","year":"2021","journal-title":"Front. Endocrinol"},{"key":"2024082806250500000_2024.08.24.609537v1.35","doi-asserted-by":"crossref","first-page":"e15099","DOI":"10.7717\/peerj.15099","article-title":"In the light of evolution:\u2019 keratins as exceptional tumor biomarkers","volume":"11","year":"2023","journal-title":"PeerJ"},{"key":"2024082806250500000_2024.08.24.609537v1.36","doi-asserted-by":"crossref","first-page":"6471","DOI":"10.1038\/s41598-021-86097-2","article-title":"Identification of oxytocin-related lncRNAs and assessment of their expression in breast cancer","volume":"11","year":"2021","journal-title":"Sci. Rep"},{"key":"2024082806250500000_2024.08.24.609537v1.37","doi-asserted-by":"crossref","unstructured":"Fiaz, T. et al. Peripheral mRNA expression and prognostic significance of emotional stress biomarkers in metastatic breast cancer patients. Int. J. Mol. Sci. 23, (2022).","DOI":"10.3390\/ijms232214097"},{"key":"2024082806250500000_2024.08.24.609537v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature06758"},{"key":"2024082806250500000_2024.08.24.609537v1.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125013"},{"key":"2024082806250500000_2024.08.24.609537v1.40","first-page":"44","article-title":"Multidisciplinary overview of vaginal atrophy and associated genitourinary symptoms in postmenopausal women","volume":"1","year":"2013","journal-title":"Sex. Med. Today"},{"key":"2024082806250500000_2024.08.24.609537v1.41","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.3390\/ijerph18094935","article-title":"Vaginal aging\u2014what we know and what we do not know","volume":"18","year":"2021","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"2024082806250500000_2024.08.24.609537v1.42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.6118\/jmm.2015.21.2.65","article-title":"The recent review of the genitourinary syndrome of menopause","volume":"21","year":"2015","journal-title":"J. Menopausal Med"},{"key":"2024082806250500000_2024.08.24.609537v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026602"},{"key":"2024082806250500000_2024.08.24.609537v1.44","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.mayocp.2017.08.019","article-title":"Genitourinary syndrome of menopause: management strategies for the clinician","volume":"92","year":"2017","journal-title":"Mayo Clin. Proc"},{"key":"2024082806250500000_2024.08.24.609537v1.45","doi-asserted-by":"publisher","DOI":"10.1210\/en.139.10.4345"},{"key":"2024082806250500000_2024.08.24.609537v1.46","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12230"},{"key":"2024082806250500000_2024.08.24.609537v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nature05610"},{"key":"2024082806250500000_2024.08.24.609537v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(00)00357-7"},{"key":"2024082806250500000_2024.08.24.609537v1.49","doi-asserted-by":"publisher","DOI":"10.1186\/S40246-022-00399-8"},{"key":"2024082806250500000_2024.08.24.609537v1.50","doi-asserted-by":"publisher","DOI":"10.1002\/path.2440"},{"key":"2024082806250500000_2024.08.24.609537v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2007.09.009"},{"key":"2024082806250500000_2024.08.24.609537v1.52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1513550112"},{"key":"2024082806250500000_2024.08.24.609537v1.53","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1186\/s12885-021-08211-x","article-title":"Identification of key pseudogenes in nasopharyngeal carcinoma based on RNA-Seq analysis","volume":"21","year":"2021","journal-title":"BMC Cancer"},{"key":"2024082806250500000_2024.08.24.609537v1.54","doi-asserted-by":"crossref","first-page":"445","DOI":"10.21037\/tcr-19-2888","article-title":"Gene expression profile of THZ1-treated nasopharyngeal carcinoma cell lines indicates its involvement in the inhibition of the cell cycle","volume":"10","year":"2021","journal-title":"Transl. Cancer Res"},{"key":"2024082806250500000_2024.08.24.609537v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.07.014"},{"key":"2024082806250500000_2024.08.24.609537v1.56","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1038\/s41467-024-45966-w","article-title":"The impact of exercise on gene regulation in association with complex trait genetics","volume":"15","author":"MoTrPAC Study Group","year":"2024","journal-title":"Nat. Commun"},{"key":"2024082806250500000_2024.08.24.609537v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2764"},{"key":"2024082806250500000_2024.08.24.609537v1.58","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2112064"},{"key":"2024082806250500000_2024.08.24.609537v1.59","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-276"},{"key":"2024082806250500000_2024.08.24.609537v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nature12172"},{"key":"2024082806250500000_2024.08.24.609537v1.61","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-5-r55"},{"key":"2024082806250500000_2024.08.24.609537v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2024082806250500000_2024.08.24.609537v1.63","unstructured":"Ebert, P. et al. Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science 372, (2021)."},{"key":"2024082806250500000_2024.08.24.609537v1.64","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"2024082806250500000_2024.08.24.609537v1.65","doi-asserted-by":"publisher","DOI":"10.4324\/9780203771587"},{"key":"2024082806250500000_2024.08.24.609537v1.66","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4218"},{"key":"2024082806250500000_2024.08.24.609537v1.67","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/GME.0b013e31829e41df","article-title":"Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors","volume":"21","year":"2014","journal-title":"Menopause"},{"key":"2024082806250500000_2024.08.24.609537v1.68","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.clbc.2015.06.012","article-title":"Vaginal gene expression during treatment with aromatase inhibitors","volume":"15","year":"2015","journal-title":"Clin. Breast Cancer"},{"key":"2024082806250500000_2024.08.24.609537v1.69","doi-asserted-by":"publisher","DOI":"10.1007\/s00239-019-09911-6"},{"key":"2024082806250500000_2024.08.24.609537v1.70","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4676-z"},{"key":"2024082806250500000_2024.08.24.609537v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/ng.687"},{"key":"2024082806250500000_2024.08.24.609537v1.72","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.79111"},{"key":"2024082806250500000_2024.08.24.609537v1.73","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.molbev.a026239"},{"key":"2024082806250500000_2024.08.24.609537v1.74","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msh010"},{"key":"2024082806250500000_2024.08.24.609537v1.75","first-page":"46","article-title":"What are the determinants of gene expression levels and breadths in the human genome? Hum","volume":"21","year":"2011","journal-title":"Mol. Genet"},{"key":"2024082806250500000_2024.08.24.609537v1.76","doi-asserted-by":"crossref","first-page":"e27477","DOI":"10.1097\/MD.0000000000027477","article-title":"Comprehensive lncRNA and mRNA profiles in peripheral blood mononuclear cells derived from ankylosing spondylitis patients by RNA-sequencing analysis","volume":"101","year":"2022","journal-title":"Medicine"},{"key":"2024082806250500000_2024.08.24.609537v1.77","unstructured":"von Grothusen C. Endometrial receptivity and regeneration in health and disease: Molecular, cellular and clinical perspectives. Karolinska Institutet (Sweden, 2022)."},{"key":"2024082806250500000_2024.08.24.609537v1.78","unstructured":"Almsned, F. M. Understanding the genetic nature of multiple sclerosis using next-generation sequencing genomic analysis methods. (Doctoral dissertation, George Mason University, 2020)."},{"key":"2024082806250500000_2024.08.24.609537v1.79","unstructured":"Chery, G. Understanding Sj\u00f6gren\u2019s Syndrome as a Systemic Autoimmune Disorder. (State University of New York at Albany, 2022)."},{"key":"2024082806250500000_2024.08.24.609537v1.80","doi-asserted-by":"crossref","first-page":"100201","DOI":"10.1016\/j.imu.2019.100201","article-title":"Detection of multiple sclerosis using blood and brain cells transcript profiles: Insights from comprehensive bioinformatics approach","volume":"16","year":"2019","journal-title":"Informatics in Medicine Unlocked"},{"key":"2024082806250500000_2024.08.24.609537v1.81","doi-asserted-by":"crossref","first-page":"e1011616","DOI":"10.1371\/journal.pcbi.1011616","article-title":"Gene communities in co-expression networks across different tissues","volume":"19","year":"2023","journal-title":"PLoS Comput. Biol"},{"key":"2024082806250500000_2024.08.24.609537v1.82","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.14.553171"},{"key":"2024082806250500000_2024.08.24.609537v1.83","doi-asserted-by":"crossref","first-page":"9064","DOI":"10.1002\/cam4.3489","article-title":"The panoramic picture of pepsinogen gene family with pan-cancer","volume":"9","year":"2020","journal-title":"Cancer Med"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.24.609537","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:56:01Z","timestamp":1768460161000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.08.24.609537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,26]]},"references-count":83,"URL":"https:\/\/doi.org\/10.1101\/2024.08.24.609537","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41467-025-60513-x","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,8,26]]},"subtype":"preprint"}}