Human cells usually contain two copies of most genes, one of which comes from the mother while the other comes from the father. It's long been thought that usually these two copies, or alleles of genes are expressed at roughly the same rate. But in recent years, scientists have also discovered genetic imprinting, in which one allele is preferentially expressed over the other. Scientists have now discovered that these alleles can actually be expressed at wildly different rates. These findings may help explain why a few people who carry disease-causing genetic mutations do not show symptoms of disease while the majority of other carriers do. The findings have been reported in Nature.
In this study, the researchers analyzed immune cells from various families, who had members with some genetic mutation that caused an immune disorder. This work showed that in sick patients, the disease causing copy, or allele, was more likely to be active. But in the healthy individuals who had inherited the same genes, the disease-causing allele was less likely to be expressed. Cells had inactivated either the maternal or paternal allele of a gene in one of every twenty genes that the cell was expressing.
There could be more plasticity in DNA that we appreciated, since every twentieth gene might be more like mom's and less like dad's, or vice versa, suggested senior study author Dusan Bogunovic, a professor at Columbia University Vagelos College of Physicians and Surgeons. “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.”
Bogunovic added that there are many diseases in which about 90 percent of carriers of a disease-causing mutation have symptoms, but there are about ten percent of carriers who do not. This work could help explain that phenomenon.
“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,” noted Bogunovic.
Although only immune cells were analyzed in this work, many genes unrelated to the immune system are also impacted. The study authors suggested that many other genetic diseases may be influenced by this phenomenon.
The investigators added that these findings may affect not only disease diagnostics but also treatments. They said that genetic diseases should not only be characterized by features in DNA, but also by how genes are expressed in the transcriptome, or the active genes being expressed in a cell. This information is found by analyzing messenger RNA transcripts in cells.
“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.
Scientists still have to learn more about how genes are selectively activated or inactivated. Some research has already pointed to epigenetic tags as one mechanism that controls genetic imprinting, but many questions remain.
Since gene expression can be controlled in cell culture, Bogunovic suggested that this approach may one day potentially be used to treat genetic diseases.