
A recent study by researchers at Columbia University, published in Nature, challenges a long-held genetic principle and provides groundbreaking insights into why some people stay symptom-free despite disease genes.
Traditionally, it is taught that every cell in the body (except reproductive cells) carries two copies of each gene—one from each parent—and that both contribute equally to cellular function. However, a recent study reveals a surprising twist: some cells can selectively inactivate one copy of a gene, either maternal or paternal, in a process called autosomal random monoallelic expression (aRMAE).
This phenomenon, identified about a decade ago, was thought to be rare and insignificant. Now, Columbia researchers have demonstrated its profound role in influencing disease outcomes. By studying immune cells from healthy individuals, researchers found that approximately 1 in 20 genes used by these cells is subject to aRMAE, meaning they express only one copy—either maternal or paternal.
Understanding the Impact on Disease Outcomes
The study focused on inborn errors of immunity (IEIs), genetic disorders that increase susceptibility to infections, autoimmune diseases, allergies, and certain cancers. IEIs often exhibit incomplete penetrance—some individuals with the same genetic mutation develop severe symptoms, while others remain unaffected.
To explore this variability, researchers analyzed families with shared genetic mutations causing IEIs but with differing clinical outcomes. They discovered that in healthy individuals, immune cells often suppressed the disease-causing gene copy. In affected family members, the same cells showed either biallelic expression (activating both copies) or selectively expressed the mutated copy.
For example:
In one family with a mutation in the PLCG2 gene, individuals with antibody deficiencies predominantly expressed the mutant allele, while healthy carriers suppressed it.
Another family with a mutation in the JAK1 gene revealed that affected members expressed both gene copies, whereas unaffected relatives expressed only the functional allele.
Similar patterns were observed in families with mutations in other genes, such as STAT1 and CARD11, demonstrating the widespread relevance of aRMAE.
Why This Discovery Matters
This research offers a new explanation for why some people with disease-causing mutations experience mild or no symptoms while others with the same genetic profile face severe health challenges.
The study also has broader implications:
It provides insights into diseases with fluctuating symptoms, such as lupus, or those triggered by environmental factors.
It could explain variations in cancer progression, where gene expression patterns play a critical role.
By showing how selective gene inactivation impacts disease outcomes, the study paves the way for more personalized approaches to understanding and managing genetic conditions.
Transforming Diagnosis and Treatment
The discovery of autosomal random monoallelic expression (aRMAE) marks a significant leap forward in understanding genetic diseases and their diverse effects. Traditionally, diagnosing these conditions has focused on identifying mutations in a person’s DNA, known as their genotype. However, this study highlights a groundbreaking concept: a person’s “transcriptotype,” or the unique activity patterns of their genes, can explain why individuals with the same genetic mutation often experience drastically different symptoms.
This shift in perspective offers profound implications for both diagnosis and treatment. By analyzing which gene copies are active or inactive in specific cells, researchers can gain a deeper understanding of why some people remain unaffected by a disease-causing mutation, while others face severe symptoms.
A Glimpse Into the Future of Treatment
Looking ahead, scientists aim to harness the mechanisms of selective gene inactivation to develop novel therapies. Imagine a future where treatments could “turn off” the defective copy of a gene while preserving the healthy one. This approach has the potential to significantly reduce, or even eliminate, the symptoms of many genetic disorders.
Though such treatments are still in the early stages of exploration, the insights from this research lay a strong foundation for these transformative possibilities. Understanding aRMAE doesn’t just enhance our knowledge of genetic diseases—it redefines how we approach them, moving beyond a static view of DNA to embrace the dynamic patterns of gene activity that shape health and disease.
This discovery represents a new frontier in medicine, offering hope for more accurate diagnoses, personalized treatments, and a brighter future for individuals affected by genetic conditions.
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