Study reveals ‘switch-like’ behavior for hundreds of genes with links to human disease microbiologystudy

Gene expression, where cells use the genetic information encoded in DNA to produce proteins, has been thought of as a dimmer light.

How much a particular gene gets expressed continually rises and falls, depending on the needs of a cell at any given time. It’s like adjusting the lighting of a room until it’s just right for your mood.

But University at Buffalo researchers have shown that a considerable portion of a human’s roughly 20,000 genes express more like your standard light switch—fully on or fully off.

The team identified nearly 500 of these “switch-like” genes, whose expression is either very high or very low, by analyzing the genes of over 900 people and across 27 different kinds of tissue. The research, described in a study published in Nature, is the first systematic analysis of switch-like genes across multiple tissues.

It ultimately points to hormones, genetic variation and epigenetic markers as potential sources of this switch-like expression.

“Understanding why we differ from each other, the sources of human diversity, is one of the fundamental questions in human genetics and anthropology. Our study provides new answers,” says the study’s co-corresponding author, Omer Gokcumen, Ph.D., professor in the UB Department of Biological Sciences, within the College of Arts and Sciences.

The study also links some of the switch-like genes to a variety of ailments and diseases, such as infertility, impaired immune response to COVID-19, and perhaps most significantly, vaginal atrophy, a condition commonly experienced by postmenopausal women.

“We believe switch-like genes could one day be used to diagnose and perhaps even treat diseases,” Gokcumen says. “Ultimately, each of us is made up of molecular ingredients produced from our genes, and our health is directly tied to the precise and precarious combination of these ingredients. Make too much or too little, and you may have disease.”

Finding switch-like genes with math

The recent availability of population-level, RNA-sequencing data from humans has made it possible to systematically identify switch-like genes from dimmer-like genes. However, the team did not originally set out to study switch-like genes.

The project started as undergraduate research supervised by the study’s other co-corresponding author, Naoki Masuda, Ph.D., professor in the Department of Mathematics. The goal was to apply a multilayer network analysis on genes to examine how different human organs are correlated as a network.

Senior math major Yanyan Li, the study’s co-first author, with the help of another senior math major, Zhiliang Wang, initially carried out this somewhat unconventional analysis, but unexpectedly identified many switch-like genes in the data.

“The 473 identified switch-like genes stood out in the dataset because they obeyed so-called bimodal distributions,” Masuda says. “Whereas a typical dimmer-like gene has unimodal distribution, a switch-like gene has two distinct peaks, corresponding to being switched on and off.”

Masuda and Gokcumen then shifted the project’s focus to switch-like genes, as they appeared to be a major part of expression variation among humans.

Switch-like genes linked to disease

The team then searched for the potential contribution of switch-like genes to disease. They found remarkable links with COVID-19, breast cancer, male infertility, implantation failure, and a very strong link with vaginal atrophy.

“Future investigations could reveal how the toggling of these genetic switches affects human diseases in general and provides new diagnostic and therapeutic tools,” says the study’s first author, Alber Aqil, a Ph.D. student in Gokcumen’s lab.

Most switch-like genes are only expressed in a switch-like manner within a single kind of tissue. Just a small percentage of the switch-like genes were universally switch-like across all the tissues examined.

The researchers propose that hormones drive tissue-specific switching, whereas universal switching is driven by an individual’s DNA.

“Hormones and DNA are two powerful factors that can push a gene into being switch-like,” Aqil says. “Typically, lots of small factors nudge a gene, causing its activity to vary, like a dimmer, but it appears that switch-like genes are controlled by one or just a few factors that have big effects.”

Other authors include Marie Saitou, a former postdoctoral fellow in Gokcumen’s lab and now an assistant professor at Norwegian University of Life Sciences in Norway; Ph.D. student Saiful Islam and former graduate student Madison Russell, both of whom worked in Masuda’s lab; and Theodora Kunovac Kallak of Uppsala University in Sweden.