“Selective Silencing”: New Research Challenges Textbook Principle of Genetics

New research uncovers why certain individuals with disease-causing genes remain symptom-free.

Researchers at Columbia University have challenged a fundamental principle of genetics, uncovering why some individuals carrying genes linked to diseases remain symptom-free.

Biology students are typically taught that every cell in the body (except sperm and eggs) contains two copies of each gene—one inherited from each parent—and that both copies contribute equally to cellular function.

However, this new study reveals that certain cells can exhibit a bias, selectively inactivating one parent’s copy of a gene. While this phenomenon was identified about a decade ago, the Columbia team has now demonstrated its potential impact on disease outcomes. By studying specific immune cells in typical individuals, the researchers found that these cells inactivated either the maternal or paternal gene copy in approximately 1 out of every 20 genes the cells use.

“This is suggesting that there is more plasticity in our DNA than we thought before,” says study leader Dusan Bogunovic, professor of pediatric immunology at Columbia University Vagelos College of Physicians and Surgeons.

“So in some cells in your body, every 20th gene can be a little bit more Mom, a little bit less Dad, or vice versa. And to make things even more complicated, this can be different in white blood cells than in the kidney cells, and it can perhaps change with time.”

The results were published Jan. 1 in the journal Nature.

Why it matters

The new study explains a longstanding puzzle in medicine: why do some people who’ve inherited a disease-causing mutation experience fewer symptoms than others with the same mutation? “In many diseases, we’ll see that 90% of people who carry a mutation are sick, but 10% who carry the mutation don’t get sick at all,” says Bogunovic, a scientist who studies children with rare immunological disorders at Columbia University Irving Medical Center.

Enlisting an international team of collaborators, the researchers looked at several families with different genetic disorders affecting their immune systems. In each case, the disease-causing copy was more likely to be active in sick patients and suppressed in healthy relatives who had inherited the same genes.

“There was some speculation that this bias toward one copy or the other could explain wide differences in the severity of a genetic disease, but no experimental evidence existed until now,” Bogunovic says.

Though the current work looked only at immune cells, Bogunovic says the selective bias for the maternal or paternal copy of a gene affected more than just immune-related genes. “We don’t see a preference for immune genes or any other class of genes, so we think this phenomenon can explain the wide variability in disease severity we see with many other genetic conditions,” he says, adding “this could be just the tip of the iceberg.”

The phenomenon could help explain diseases with flares, like lupus, or those that emerge following environmental triggers. It could also play a role in cancer.

Changing the future of treatments for genetic diseases?

The study’s findings point to an entirely new paradigm for diagnosing and perhaps even treating inherited diseases.

The investigators propose expanding the standard characterization of genetic diseases to include patients’ “transcriptotypes,” their gene activity patterns, in addition to their genotypes.

“This changes the paradigm of testing beyond your DNA to your RNA, which as we’ve shown in our study, is not equal in all cell types and can change over time,” says Bogunovic.

If researchers can identify the mechanisms behind selective gene inactivation, they may also be able to treat genetic diseases in a new way, by switching a patient’s gene expression pattern to suppress the undesirable copy. While emphasizing that such strategies are still far from clinical use, Bogunovic is optimistic: “At least in cell culture in the lab, we can do it, so manipulation in that way is something that could turn somebody’s genetic disease into non-disease, assuming we are successful.”

Reference: “Monoallelic expression can govern penetrance of inborn errors of immunity” by O’Jay Stewart, Conor Gruber, Haley E. Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P. Hoytema van Konijnenburg, Ivan K. Chinn, Luis A. Pedroza, James R. Lupski, Erica G. Schmitt, Megan A. Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S. Orange, Jean-Laurent Casanova, Joshua D. Milner and Dusan Bogunovic, 1 January 2025, Nature.
DOI: 10.1038/s41586-024-08346-4

The study was funded by the National Institutes of Health.

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