Differences in the physiology and function of cells across our body are determined by gene expression and subsequent protein production.<\/p>\n
A new study by scientists at the University of Buffalo has found that hundreds of human genes are expressed in a \u201csurprisingly binary\u201d fashion. The research is published in Nature Communications<\/a>.<\/p>\n Rethinking gene expression: From dimmers to switches<\/b><\/p>\n The way scientists study DNA, genomes and the central dogma of biology \u2013 the flow of genetic information from genes to proteins \u2013 is continually evolving. Over recent decades, the analogy of a dimmer switch has predominantly been used to describe gene expression, whereby genetic activity can increase or decrease depending on a cell\u2019s needs from one moment to the next.<\/p>\n But in their new paper, the Buffalo researchers found that hundreds of human genes function like standard light switches \u2013 they are \u201con\u201d in some people and \u201coff\u201d in others, otherwise known as \u201cswitch-like\u201d genes.<\/p>\n \u201cSwitch-like genes are genes that are highly expressed in some individuals, nearly silent in others, and rarely show intermediate levels,\u201d Dr. Naoki Masuda<\/a>, a former professor of mathematics at the University of Buffalo, and the study\u2019s lead author, told Technology Networks.<\/p><\/blockquote>\n Masuda and colleagues conducted a systematic analysis of switch-like genes by analyzing genomes, transcriptomes and methylomes from 943 individuals and 27 different tissues using the Genotype-Tissue Expression (GTEx) Project database<\/a>. The team was particularly interested in systematically identifying genes that have biomedical relevance.<\/p>\n \u201cHow much a gene is turned on, or how much of its product it makes, is a major factor in determining health and biological function. Most traits in humans (like height or cholesterol) follow a bell-shaped curve: most people fall in the middle and only a few are at the extremes. Gene expression usually behaves the same way,\u201d Dr. Omer Gokcumen<\/a>, professor of biology at Buffalo, and study co-author, said. \u201cBut we asked: Are there any genes that don\u2019t follow that smooth curve?\u201d<\/p>\n What is the GTEx database?\u00a0 <\/b><\/p>\n The GTEx Project is a comprehensive resource<\/a> built for researchers to study human gene expression, regulation and its relationship to genetic variation, across diverse tissues and individuals.<\/p>\n Historically, studies of switch-like genes have focused on cancerous or skeletal muscle tissue, limiting our understanding of their dynamics across different types of tissue. Systematic analyses simply haven\u2019t been feasible due to the lack of comprehensive databases, Gokcumen explained: \u201cThe GTEx database has only recently reached the sample sizes needed to systematically identify such patterns.\u201d <\/p>\n Switch-like genes offer new insights into disease risk and women\u2019s health<\/b><\/p>\n Using the GTEx project database, Masuda and colleagues identified 473 switch-like genes in total. Only 40 genes acted like \u201con\u201d or \u201coff\u201d switches in every tissue \u2013 the rest switch \u201con\u201d or \u201coff\u201d only in certain tissues. Masuda and colleagues suggest that hormones may drive tissue-specific switching, while methylation analysis suggests epigenetic silencing underpins universal switching.<\/p>\n \u201cUsing statistical models, we found a set of genes that are either fully \u2018on\u2019 or completely \u2018off\u2019 in different individuals. These switch-like genes are rare but important. Our results suggest that this kind of all-or-nothing variation isn\u2019t just a curiosity. It\u2019s often connected to disease risk and may represent a previously overlooked layer of human genetic diversity,\u201d said Gokcumen.<\/p>\n The study insights could support the development of more efficient screening methods. \u201cIf we find a variant that turns a protective gene \u2018off\u2019, a simple DNA test from a cheek swab could flag higher risk,\u201d said Alber Aqil<\/a>, a PhD candidate in Gokcumen\u2019s lab and the study\u2019s first author. \u201cFor instance, an \u2018off\u2019 state in the genes\u00a0CYP4F24P\u00a0and\u00a0GPX1P1\u00a0is linked to greater odds of nasopharyngeal cancer. As more evidence of these genes\u2019 connection to cancer comes through, genotyping those sites could become a screening tool \u2013 much like\u00a0BRCA\u00a0tests for breast cancer today.\u201d<\/p>\n Systematically analyzing switch-like genes could also advance women\u2019s health research, an area of significant unmet clinical need.<\/p>\n The Buffalo team identified a set of genes that are typically active in vaginal tissue, which seem to switch \u201coff\u201d after menopause in some women. This may contribute to the development of vaginal atrophy, a condition characterized by thinning, drying and inflammation of the vaginal walls.<\/p>\n \u201cWhen estrogen therapy is used, these genes switch back on and the symptoms of vaginal atrophy subside,\u201d Aqil said. \u201cIf certain women already have slightly low expression levels of these genes before menopause, it is conceivable that they can be at a higher risk of vaginal atrophy after menopause. Testing this formally could be an interesting area of research.\u201d<\/p><\/blockquote>\n Other switch-like genes were connected to health issues, including infertility and a weakened immune response to COVID-19. <\/p>\n Identifying new forms of switch-like regulation<\/b><\/p>\n By offering a new way to study gene expression, the researchers hope their analyses could one day better predict disease risk and improve patient care.<\/p>\n While the current study focuses on gene expression levels, genes can produce different isoforms through a process called alternative splicing<\/a>. \u201cIn some cases, one isoform may dominate in certain individuals, while a different isoform dominates in others,\u201d Aqil said. \u201cIdentifying such cases systematically could reveal new forms of switch-like regulation. A key question is whether these individual-specific isoform patterns are linked to differences in disease risk or other phenotypic traits.\u201d The research group\u2019s next step will, therefore, be to extend the switch-like framework to RNA splicing.<\/p>\n \u201cIn this article, we only highlighted a small fraction of the switch-like genes we found,\u201d added Masuda.<\/p>\n \u201cMore thorough investigation of various switch-like genes in health and disease, especially in cancer, for which some switch-like genes have been documented by other parties but not systematically, is also an outstanding next step,\u201d he concluded.<\/p>\n