Summary: New research from Columbia University shows that some cells preferentially inactivate one parent’s copy of a gene, producing a bias in gene activity called monoallelic expression. This selective inactivation affects roughly one in twenty genes in the immune cells studied and helps explain why some people who carry disease-causing mutations have little or no symptoms. The finding reshapes how we think about genetic penetrance and suggests new diagnostic and therapeutic directions for inherited disorders.
Researchers found that the active copy of a gene in a cell can determine whether a person with a mutation develops disease. This selective gene inactivation varies by cell type and may change over time, which could account for variable disease severity among relatives who share the same mutation.
Key Facts:
- Gene Inactivation: Individual cells can silence either the maternal or paternal copy of a gene, producing biased expression that influences cellular function.
- Disease Variability: Whether the mutant or the healthy allele is expressed can determine the severity of inherited diseases or whether symptoms appear at all.
- Treatment Potential: Understanding mechanisms of monoallelic expression may open therapeutic opportunities to shift gene activity toward the healthy allele.
Source: Columbia University
Columbia researchers report findings that challenge a traditional genetics assumption and illuminate why some carriers of genetic mutations remain healthy.
Biology texts teach that most body cells carry two copies of each autosomal gene—one inherited from each parent—and that both copies usually contribute equally. The new study, however, demonstrates that many genes can be subject to a bias in expression, with one parental allele silenced in specific cells. This phenomenon, known as autosomal random monoallelic expression (aRMAE), was previously observed but is now shown to have direct relevance for human disease.
The Columbia team examined immune cells from healthy individuals to estimate how often monoallelic expression occurs in those cell types. They found that approximately one out of every 20 genes used by these immune cells shows a bias where either the maternal or paternal allele is preferentially expressed while the other is silenced. Study leader Dusan Bogunovic, professor of pediatric immunology at Columbia University Vagelos College of Physicians and Surgeons, highlights the implication: DNA expression is more flexible and context-dependent than previously believed.
“In some cells throughout the body, roughly every twentieth gene can be more influenced by the maternal copy or the paternal copy, and this balance can differ between cell types—white blood cells versus kidney cells, for example—and may also shift over time,” Bogunovic explains.
The study’s results were published Jan. 1 in the journal Nature.
Why it matters
These findings address a long-standing clinical puzzle: why individuals who inherit the same disease-causing mutation often show very different clinical outcomes. In many genetic diseases, most carriers develop symptoms while a minority remain healthy. The research shows that this variability can stem from which allele—mutant or wild-type—is active in disease-relevant cells.
To explore this, the investigators analyzed families in which relatives shared the same immune-system mutations but had different clinical presentations. In affected family members, the mutant allele tended to be the active one in the relevant immune cells, whereas in unaffected relatives the mutant allele was more often suppressed. These observations provide direct experimental evidence that allele-specific expression bias can influence disease penetrance.
Although this study focused on immune cells and inborn errors of immunity, the researchers did not detect any preference for particular gene classes. That suggests monoallelic expression may help explain variable penetrance across a wide range of genetic conditions, potentially including flare-prone autoimmune diseases and some cancers.
Changing the future of treatments for genetic diseases?
This research points toward a new clinical paradigm that would consider not only a patient’s genotype but also their “transcriptotype”—the pattern of gene activity across cell types. Including RNA-based assessments alongside DNA testing could improve diagnosis and risk prediction for inherited disorders.
If scientists can identify and control the mechanisms that commit a cell to express one allele over the other, it may become possible to shift expression away from a harmful allele and toward a healthy one. While such interventions remain experimental and distant from routine clinical use, the authors demonstrate in laboratory cell systems that allele expression patterns can be altered, suggesting a potential therapeutic avenue.
Additional information
The study is titled “Monoallelic expression can govern penetrance of inborn errors of immunity,” and was published Jan. 1 in Nature. The work explores how autosomal random monoallelic expression contributes to incomplete penetrance in monogenic immune disorders and documents cases in which allele-specific expression correlates with clinical status among relatives.
All authors: O’Jay Stewart (Columbia), Conor Gruber (Icahn School of Medicine at Mount Sinai), Haley E. Randolph (Columbia), Roosheel Patel (Icahn School of Medicine at Mount Sinai), Meredith Ramba (Columbia), Enrica Calzoni (Columbia), Lei Haley Huang (Columbia), Jay Levy (Columbia), Sofija Buta (Columbia), Angelica Lee (Columbia), Christos Sazeides (Columbia), Zoe Prue (Columbia), David P. Hoytema van Konijnenburg (Boston Children’s Hospital and Harvard Medical School), Ivan K. Chinn (Baylor College of Medicine and Texas Children’s Hospital), Luis A. Pedroza (Columbia), James R. Lupski (Baylor), Erica G. Schmitt (Washington University School of Medicine), Megan A. Cooper (Washington University School of Medicine), Anne Puel (INSERM, University of Paris Cité, Necker Hospital for Sick Children), Xiao Peng (Johns Hopkins), Stéphanie Boisson-Dupuis (INSERM, University of Paris Cité, Necker Hospital for Sick Children), Jacinta Bustamante (INSERM, University of Paris Cité, Necker Hospital for Sick Children, Rockefeller University), Satoshi Okada (Hiroshima University), Marta Martin-Fernandez (Columbia and Instituto de Salud Carlos III), Jordan S. Orange (Columbia), Jean-Laurent Casanova (INSERM, University of Paris Cité, Necker Hospital for Sick Children, Rockefeller University, and Howard Hughes Medical Institute), Joshua D. Milner (Columbia) & Dusan Bogunovic (Columbia).
About this genetics research news
Author: Helen Garey
Source: Columbia University
Contact: Helen Garey – Columbia University
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Monoallelic expression can govern penetrance of inborn errors of immunity” by Dusan Bogunovic et al., Nature.
Abstract
Monoallelic expression can govern penetrance of inborn errors of immunity
Inborn errors of immunity (IEIs) are genetic disorders that cause susceptibility to infection, autoimmunity, autoinflammation, allergy and malignancy. Despite their monogenic origins, many IEIs show incomplete penetrance and variable expressivity.
This study examines the role of autosomal random monoallelic expression (aRMAE)—a somatic commitment by cells to express one allele—in contributing to phenotypic variability in families with IEIs. Using a clonal primary T cell system from healthy individuals, the authors estimate that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE in the cell types studied.
Experimental perturbation of chromatin marks (H3K27me3) and DNA methylation changed allelic expression commitment, supporting two proposed mechanisms that regulate aRMAE. Clinical samples from individuals with shared genetic lesions but discordant phenotypes revealed allele-specific expression patterns that aligned with disease status.
For example, among relatives heterozygous for a PLCG2 deletion (delEx19), antibody deficiency correlated with selective expression of the mutant allele in B cells. In another family, relatives heterozygous for a JAK1 mutation (c.2099G>A; p.S700N) showed that the unaffected carrier’s T cells predominantly expressed the wild-type JAK1 allele, while the affected carrier’s T cells exhibited biallelic expression. Similar allelic biases were documented in families with STAT1 and CARD11 mutations.
Overall, the study underscores the importance of integrating both genotype and “transcriptotype”—the cell-specific pattern of allele expression—into analyses of penetrance and expressivity in monogenic disorders.