Hundreds of Human Genes Show “Switch-Like” Behavior

Differences in the physiology and function of cells across our body are determined by gene expression and subsequent protein production.

A new study by scientists at the University of Buffalo has found that hundreds of human genes are expressed in a “surprisingly binary” fashion. The research is published in Nature Communications.

Rethinking gene expression: From dimmers to switches

The way scientists study DNA, genomes and the central dogma of biology – the flow of genetic information from genes to proteins – 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’s needs from one moment to the next.

But in their new paper, the Buffalo researchers found that hundreds of human genes function like standard light switches – they are “on” in some people and “off” in others, otherwise known as “switch-like” genes.

“Switch-like genes are genes that are highly expressed in some individuals, nearly silent in others, and rarely show intermediate levels,” Dr. Naoki Masuda, a former professor of mathematics at the University of Buffalo, and the study’s lead author, told Technology Networks.

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. The team was particularly interested in systematically identifying genes that have biomedical relevance.

“How 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,” Dr. Omer Gokcumen, professor of biology at Buffalo, and study co-author, said. “But we asked: Are there any genes that don’t follow that smooth curve?”

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’t been feasible due to the lack of comprehensive databases, Gokcumen explained: “The GTEx database has only recently reached the sample sizes needed to systematically identify such patterns.”

Switch-like genes offer new insights into disease risk and women’s health

Using the GTEx project database, Masuda and colleagues identified 473 switch-like genes in total. Only 40 genes acted like “on” or “off” switches in every tissue – the rest switch “on” or “off” only in certain tissues. Masuda and colleagues suggest that hormones may drive tissue-specific switching, while methylation analysis suggests epigenetic silencing underpins universal switching.

“Using statistical models, we found a set of genes that are either fully ‘on’ or completely ‘off’ in different individuals. These switch-like genes are rare but important. Our results suggest that this kind of all-or-nothing variation isn’t just a curiosity. It’s often connected to disease risk and may represent a previously overlooked layer of human genetic diversity,” said Gokcumen.

The study insights could support the development of more efficient screening methods. “If we find a variant that turns a protective gene ‘off’, a simple DNA test from a cheek swab could flag higher risk,” said Alber Aqil, a PhD candidate in Gokcumen’s lab and the study’s first author. “For instance, an ‘off’ state in the genes CYP4F24P and GPX1P1 is linked to greater odds of nasopharyngeal cancer. As more evidence of these genes’ connection to cancer comes through, genotyping those sites could become a screening tool – much like BRCA tests for breast cancer today.”

Systematically analyzing switch-like genes could also advance women’s health research, an area of significant unmet clinical need.

The Buffalo team identified a set of genes that are typically active in vaginal tissue, which seem to switch “off” 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.

“When estrogen therapy is used, these genes switch back on and the symptoms of vaginal atrophy subside,” Aqil said. “If 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.”

Other switch-like genes were connected to health issues, including infertility and a weakened immune response to COVID-19.

Identifying new forms of switch-like regulation

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.

While the current study focuses on gene expression levels, genes can produce different isoforms through a process called alternative splicing. “In some cases, one isoform may dominate in certain individuals, while a different isoform dominates in others,” Aqil said. “Identifying 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.” The research group’s next step will, therefore, be to extend the switch-like framework to RNA splicing.

“In this article, we only highlighted a small fraction of the switch-like genes we found,” added Masuda.

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“More 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,” he concluded.

Reference: Aqil A, Li Y, Wang Z, et al. Switch-like gene expression modulates disease risk. Nat Comms. 2025;16(1):5323. doi: 10.1038/s41467-025-60513-x

Meet the interviewees:

Omer Gokcumen, PhD

Omer Gokcumen, PhD, is a professor of biological sciences at the
University at Buffalo, where he leads a pioneering research program focused on
the evolutionary and functional impact of genomic structural variation in
humans and other mammals. Trained at Harvard and the University of Pennsylvania
as a biological anthropologist and genomic scientist, Dr. Gokcumen brings a
rare interdisciplinary lens that combines evolutionary biology, population
genetics, functional genomics, and anthropology to understand what makes us human
and how our evolutionary history shapes our present.

Naoki Masuda, PhD

Naoki Masuda, PhD, was a professor of mathematics at the
Institute for Artificial Intelligence and Data Science at the University at
Buffalo at the time the paper was published. He is currently a professor at the
Gilbert S. Omenn Department of Computational Medicine and Bioinformatics and
the Department of Mathematics at the University of Michigan. His research
interests include network science and mathematical biology. He particularly
focuses on temporal networks, analysis of biological and medical network data,
models of contagion processes and random walks on networks.

Alber Aqil

Alber Aqil
is a PhD candidate in Omer Gokcumen’s lab.