Genetic Disease Variability

New Insight into Genetic Disease Variability

New research reveals that certain cells inactivate one parent’s copy of a gene, leading to a bias in gene activity that may explain why some individuals with disease-causing mutations remain symptom-free. This selective gene inactivation, known as monoallelic expression, affects about 1 in 20 genes and varies between cell types.

The study shows that in families with genetic disorders, the active copy of a gene often determines disease severity. These findings challenge traditional genetic paradigms and suggest new approaches to diagnosing and treating inherited diseases.

Key Facts:

Gene Inactivation: Cells can selectively inactivate one parent’s gene copy, influencing disease outcomes.

Disease Variability:

Active copies of genes determine the severity or absence of symptoms in genetic disorders.

Treatment Potential:

Understanding this phenomenon could lead to therapies that adjust gene expression patterns.

Every biology student learns that each cell in our body (except sperm and eggs) contains two copies of each gene, one from each parent, and each copy plays an equal part in the cell.

The new study shows that some cells are often biased when it comes to some genes and inactivate one parent’s copy. The phenomenon was discovered about a decade ago, but the new study shows how it can influence disease outcomes.

The Columbia researchers looked at certain immune cells of ordinary people to get an estimate of the phenomenon and found that these cells had inactivated the maternal or paternal copy of a gene for one out of every 20 genes utilized by the cell.

“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 thing 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.