Are there certain genes that can “switch” diseases on and off? (© JEGAS RA
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In a nutshell
- Scientists identified 473 “switch-like” genes that act more like on/off light switches than dimmers — either fully active or completely silent.
- These genetic switches are linked to risks for cancers, immune conditions, metabolic diseases, and skin disorders, and could help doctors spot disease risk before symptoms appear.
- The switches are controlled by genetic variations, hormones, and chemical changes like DNA methylation, opening new doors for personalized treatments that might flip the right switches back on or off.
BUFFALO, N.Y. — Your genes don’t all behave the same way. While most gradually turn up or down their activity like a dimmer switch, some act more like light switches, either completely “on” or completely “off.” Scientists have now identified 473 of these switch-like genes that could help doctors predict your risk for cancer, autoimmune diseases, and other serious health conditions years before symptoms appear.
Researchers analyzed genetic data from nearly 1,000 people across 27 different body tissues and published their findings in Nature Communications. These biological switches create what scientists call “bimodal expression,” meaning they’re either fully active or completely silent in different people, with no middle ground.
Doctors might soon examine your unique genetic “switch settings” during routine check-ups to spot disease risk early. These genetic switches appear to be master controllers that can flip entire networks of genes on or off simultaneously.
The researchers found these switch-like genes were enriched for associations with cancers and immune, metabolic, and skin diseases.
Could doctors one day “flip the switch” on cancer-causing genes? (© RFBSIP – stock.adobe.com)
How Scientists Identified These Genetic Switches
Researchers from the State University of New York at Buffalo analyzed genetic expression data from the GTEx database, which contains tissue samples from 943 individuals who donated their bodies to science. Rather than examining DNA sequences, this research looked at which genes were actually active in different tissues.
As noted, the team found that 473 genes behaved like traditional on/off switches instead of dimmers we use to control lighting in a room. In any given person, these genes were either highly active or completely silent.
These genetic switches don’t operate randomly. Many are controlled by common genetic variations — differences in DNA inherited from parents. Some switches are controlled by large deletions where entire gene segments are missing, while others are regulated by single-letter changes in the genetic code.
Master Switches Control Multiple Genes at Once
Switch-like genes don’t work alone. In certain tissues, particularly the breast, colon, and vagina, multiple genetic switches tend to flip on or off together, controlled by master regulatory mechanisms.
In breast tissue, researchers found that 157 out of 158 tissue-specific switch-like genes showed female-biased expression, meaning they were more likely to be “on” in women than men. Many of these genes, including those involved in cancer development, appeared to be controlled by hormonal signals.
The vagina showed an even more dramatic pattern. Seven genes linked to vaginal atrophy — a condition affecting nearly half of postmenopausal women — switched off together in many individuals. When researchers examined vaginal tissue samples, they discovered that low estrogen levels caused these genes to shut down simultaneously, leading to the thinning of vaginal tissue.
By examining structural variations in human genomes, researchers traced the origins of many genetic switches. They found that 41% of universal switch-like genes (those that behave the same way across all body tissues) are caused by large-scale DNA changes like deletions, duplications, or insertions.
One example involves two genes called USP32P2 and FAM106A. A common deletion that occurs in about 25% of the global population completely removes both genes. People who inherit this deletion from both parents have these genes permanently switched off in every tissue.
This genetic deletion might have health consequences. The researchers note that under-expression of the gene USP32P2 in sperm is associated with male infertility, and the gene FAM106A interacts with SARS-CoV-2 and is downregulated after infection. The study suggests that individuals with FAM106A already switched off may develop more severe COVID-19 symptoms upon infection.
Chemical Modifications Control the Switches
So how are these genetic switches are controlled at the molecular level? DNA methylation, a chemical modification that can silence genes, plays a crucial role in the behavior. When researchers analyzed methylation patterns in switch-like genes, they found that 30% showed strong negative correlations between methylation levels and gene activity.
DNA methylation matters because environmental factors can affect these patterns and potentially flip genetic switches. In breast tissue, 71 out of 73 switch-like genes showing methylation correlations were found in this single tissue type, suggesting that breast tissue may be especially susceptible to environmental regulation.
A portrait of (from left) Naoki Masuda, with the department of mathematics, Alber Aquil, and Omer Gokcumen, both with the department of biological sciences. The group recently worked on a paper and were photographed in May 2025 in the Natural Sciences Complex. (Photographer: Meredith Forrest Kulwicki)
Beyond genetic factors, the study revealed that age and hormones can affect genetic switches. In uterine tissue, researchers found two genes whose switch states correlated with age, potentially explaining why fertility declines as women get older.
Sex hormones, particularly estrogen, emerged as powerful switch controllers. The coordinated switching of multiple genes in response to estrogen levels means hormonal therapies could potentially be designed to flip specific genetic switches on or off, offering more targeted treatments for hormone-related conditions.
Doctors might soon be able to use genetic switch profiles to assess disease risk long before symptoms appear. Since many switch-like genes are enriched in cancer-related pathways, a person’s unique switch configuration could help identify their cancer susceptibility. The finding that switches often work in coordinated networks also means that targeting master regulatory mechanisms could be more effective than trying to control individual genes.
For conditions like vaginal atrophy, hormone replacement therapy that activates the right genetic switches might be more precisely tailored to individual patients. The identification of 473 genetic switches represents just the beginning of how these biological circuits control human health and disease. As researchers develop better tools to measure and manipulate these switches, we may be entering an era where doctors can literally flip the genetic switches that determine our disease destiny.
Paper Summary
Methodology
Researchers analyzed gene expression data from the GTEx database, which contains tissue samples from 943 individuals across 27 different body tissues. They used a statistical test called the “dip test” to identify genes with bimodal (switch-like) expression patterns, meaning genes that were either highly active or completely silent across different people, rather than showing gradual variations. The team also analyzed DNA methylation patterns and genetic variations to understand what controls these switches. They corrected for technical factors that could create false bimodal patterns and used strict statistical thresholds to ensure their findings were robust.
Results
The study identified 473 switch-like genes, with only 8.5% showing switch-like behavior across all tissues (universal switches) while the majority were tissue-specific. Universal switches were largely controlled by genetic variations like deletions or mutations, while tissue-specific switches appeared to be controlled by hormones and environmental factors. Switch-like genes were enriched in pathways related to cancer, immune function, metabolism, and skin development. In vaginal tissue, seven switch-like genes linked to vaginal atrophy switched off together in response to low estrogen levels. DNA methylation was found to control switch behavior in about 30% of cases, particularly in breast tissue.
Limitations
The study analyzed gene expression at the RNA level, which doesn’t always correspond to protein levels due to post-transcriptional regulation. The research was limited to tissues available in the GTEx database and couldn’t examine all possible tissue types. Some genetic variations underlying universal switch behavior remain unidentified, likely requiring more advanced sequencing technologies to detect. The study also couldn’t establish direct causal relationships between switch states and disease outcomes, only correlations with disease-associated pathways.
Funding and Disclosures
The research was supported by grants from the National Institute of General Medical Sciences, National Science Foundation, Japan Science and Technology Agency, and JSPS KAKENHI. The authors declared no competing interests. Vaginal tissue analysis was conducted under approval from the Regional Ethical Review Board in Uppsala, Sweden.
Publication Information
The study “Switch-like gene expression modulates disease risk” was published in Nature Communications on June 18, 2025 (volume 16, article 5323). The research was led by investigators from the State University of New York at Buffalo, Uppsala University in Sweden, and the Norwegian University of Life Sciences, with corresponding authors Omer Gokcumen and Naoki Masuda.