The COVID-19 pandemic clearly demonstrated that people respond to the same infection in completely different ways. Some develop mild symptoms, while others face serious complications. This diversity of reactions raises an important question: why do two individuals exposed to the same pathogen differ so greatly in their response?
The secret lies in the differences in genetic code and life experience, which influence cell behavior during epigenetic modifications. These molecular changes help determine which genes are active and which are not, thereby shaping cell function without altering the DNA.
A team of scientists from the Salk Institute has created an extensive epigenetic catalog that illustrates how hereditary traits and life events affect various types of immune system cells. This catalog, published in the journal Nature Genetics on January 27, 2026, provides new insights into the reasons for the diversity of immune responses in people and suggests directions for the development of specific therapies.
“Our immune cells record molecular notes about our genes and life experiences. These two aspects shape the immune system in different ways,” says Joseph Ecker, the senior author of the study and a professor in the Department of Genetics at the Salk Institute. “This work demonstrates that infections and environmental factors can leave lasting epigenetic marks that influence immune cell activity. By studying this influence at the level of individual cells, we can begin to link genetic and epigenetic risks to specific immune system cells where disease begins.”
Epigenome: what it is and why it matters
Every cell in the body contains the same DNA; however, cells can vary significantly in appearance and function. This diversity is partially governed by epigenetic markers—tiny molecular tags that attach to DNA and regulate gene activity. All these markers make up the cell's epigenome.
Unlike DNA, the epigenome can change over time. Some epigenetic characteristics are formed as a result of heredity, while others are influenced by life experience. Both of these factors affect immune system cells, but it has not been clear how exactly they influence the formation of epigenetic changes.
“Discussions about heredity and environment are a long-standing topic in both biology and society,” says Wenliang Wang, one of the co-authors of the study. “We aimed to understand how these two aspects manifest in immune system cells and their impact on human health.”
How life experience leaves a mark on immune cells
To analyze the influence of genetics and life experience, the research team studied blood samples from 110 patients with varying profiles. These samples reflected a wide range of genetic variants and life experiences, including exposures to different infections and vaccinations.
The scientists examined four main types of immune system cells, including long-lived T-lymphocytes and B-lymphocytes with long-term immune memory, as well as monocytes and natural killer cells that respond quickly to threats. By comparing the epigenetic data of these cells, the team created an extensive catalog of epigenetic markers for each type.
“We found that genetic variants associated with diseases often affect DNA methylation in specific types of cells,” explains Ubin Ding, one of the authors of the study. “Mapping these connections allows us to more accurately identify which cells and molecular pathways may be affected by genes associated with disease risk, opening new avenues for targeted therapy.”
Separating epigenetic changes by source
One of the main achievements of the study was the separation of epigenetic changes into those associated with genetics (gDMR) and those caused by life experience (eDMR). The scientists found that these two types of markers are concentrated in different areas of the epigenome. Genetically inherited changes were more frequently found in stable gene regions, particularly in long-lived T- and B-lymphocytes, while experience-related changes were concentrated in flexible regulatory regions that control rapid immune responses.
These patterns suggest that genetics lays the foundation for long-term immune response programs, while experience helps adapt the response of immune cells to specific conditions. Further research is needed to fully understand how these factors influence the immune system in health and disease.
“Our atlas of immune system cells will be a valuable resource for future research into the mechanisms of infectious and genetic diseases, including diagnostics and prognostics,” adds Manoj Hariharan, another co-author of the study. “Often, when a person becomes ill, we cannot immediately determine the cause and severity. Our epigenetic markers could serve as a basis for classifying and assessing such situations.”
Prospects for disease prediction and personalized medicine
The results of the study highlight how significantly genetics and life experience shape the identity and functioning of immune system cells. The new catalog could serve as a foundation for developing a personalized approach to treatment and prevention.
Ecker notes that as new patient data samples accumulate, this could help predict their response to future infections. For example, if a sufficient amount of data is collected from COVID-19 patients, researchers will be able to identify common protective eDMRs in those who have already recovered from the infection. Doctors could then analyze the immune cells of newly infected individuals to check for the presence of these protective markers. If they are absent, scientists could focus on adjacent regulatory pathways to improve treatment.
“Our work lays the groundwork for developing highly precise strategies for preventing infectious diseases,” concludes Wang. “Regarding COVID-19, influenza, and many other infections, we will be able to predict how a person will respond to an infection even before it occurs, thanks to growing cohorts and models. We will be able to use the genome to predict the impact of infection on the epigenome and then assess how these changes will affect symptoms.”
The study was supported by the Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health, and the National Science Foundation.
