How Cells Choose Between Mom’s or Dad’s Genes and Impact Disease

What occurs when cells lean more toward one parent's genes than the other? And why do some individuals who inherit disease-causing genetic mutations from their parents remain unaffected, while others with the same mutation experience debilitating symptoms?

These questions have puzzled scientists and doctors for decades, but a new study published in Nature may have some answers. Led by researchers at Columbia University, the study challenges traditional genetic principles by uncovering the role of monoallelic expression (MAE) in determining how genetic diseases manifest.

Monoallelic expression and its impact on genetic disorders

Every biology student learns that our cells, except for sperm and eggs, contain two copies of each gene – one inherited from each parent. Traditionally, it’s been assumed that both copies play an equal role in a cell's function. However, research in recent years has shown this isn’t always the case.

Some cells exhibit a bias, selectively inactivating one parent’s copy of a gene. Although this phenomenon, known as MAE, was first identified over a decade ago, its potential to influence disease outcomes has only recently come into focus.

“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,” said corresponding author Dr. Dusan Bogunovic, a pediatric immunologist at Columbia University Irving Medical Center.

This discovery is particularly relevant to inborn errors of immunity (IEIs), a group of genetic disorders that compromise the immune system, leading to susceptibility to infections, autoimmune diseases, inflammation, allergies and cancer. With over 450 genes linked to IEIs, the spectrum of symptoms and severity varies widely even among individuals carrying the same genetic mutation. IEIs are typically considered monogenic diseases – caused by a single gene mutation. In theory, the presence of a mutation should lead to predictable outcomes. However, in practice, some carriers remain asymptomatic while others experience life-threatening conditions.

Understanding how MAE affects IEIs helps explain why these disorders can look so different from one person to the next.

Mapping MAE in immune cells

To investigate the phenomenon, Bogunovic and the team used a novel experimental approach involving clonal primary T cells derived from healthy donors. By isolating and expanding single T cells, they could assess gene expression at the level of individual alleles. This method allowed the team to map MAE across thousands of genes, focusing on immune-related genes linked to IEIs. Advanced RNA sequencing technology helped determine which parental copy of a gene was active in each cell.

The study revealed that MAE occurs in approximately 5% of genes in immune cells, with cells randomly favoring either the maternal or paternal gene copy. This selective gene activation varied not only by cell type but also over time.

The researchers highlighted the link between MAE and differences in disease severity in individuals with mutations in genes like STAT1 and CARD11. In one case, individuals with the same mutation showed vastly different symptoms because of how MAE influenced which copy of the gene was expressed.

“This is suggesting that there is more plasticity in our DNA than we thought before. 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 kidney cells, and it can perhaps change with time.”
Dr. Dusan Bogunovic

The team emphasized that MAE is not restricted to 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,” said Bogunovic.

“This could be just the tip of the iceberg.”

Transforming genetic disease diagnosis and treatment

The finding that MAE influences disease severity provides insight into understanding why people with the same genetic mutation often experience dramatically different outcomes.

“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,” said Bogunovic.

The implications of the study stretch beyond just immune-related disorders. The ability to understand and measure how genes are activated in different cells – known as transcriptotyping – represents an important change in genetic diagnostics. Traditionally, genetic testing has focused primarily on genotypes, the DNA sequence itself, to determine disease risks.

“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,” said Bogunovic.

By measuring gene activity patterns – the transcriptotype – clinicians could potentially predict disease risk with greater accuracy, especially in cases where genetic mutations alone do not fully explain disease severity.

The results also offer a new avenue for therapeutic strategies. If researchers can manipulate gene expression to suppress harmful alleles, it might be possible to turn off the genetic defect, leading to a “non-disease” state.

“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,” said Bogunovic.

These findings suggest that the future of genetic diagnostics and treatments will likely hinge on understanding not just the genetic code, but also how it is expressed at the cellular level, leading to more personalized approach to managing genetic disorders.

Reference: Stewart O, Gruber C, Randolph HE, et al. Monoallelic expression can govern penetrance of inborn errors of immunity. Nature. 2025. doi: 10.1038/s41586-024-08346-4

This article is a rework of a press release issued by Columbia University Irving Medical Center. Material has been edited for length and content.