More Than Just Two Copies
Humans typically inherit two copies of nearly every gene, one from each biological parent. For most genes, both copies are active, providing a biological safeguard if one copy has a minor variation. However, for a small subset of genes, only one copy is active, depending on which parent it was inherited from. This phenomenon is known as genomic imprinting.
The Epigenetic Signature
Gene imprinting is regulated by molecular modifications that do not alter the underlying DNA sequence. These modifications are known as epigenetic marks that dictate gene activity. A primary mechanism involves DNA methylation, where a methyl group, a small chemical tag, is added to specific cytosine bases within a gene’s regulatory regions. This addition typically acts as a signal to silence the gene, preventing its expression.
These epigenetic imprints are established during gametogenesis, the process of forming sperm and egg cells. During this period, the parental genome undergoes a reprogramming phase where existing epigenetic marks are erased and new, parent-specific patterns are laid down. For example, a particular gene might be methylated and silenced only when inherited from the father, while the maternally inherited copy remains active. These imprints are then maintained through cell division during embryonic development and throughout an individual’s life.
Specific enzymes called DNA methyltransferases (DNMTs) play a role in establishing and maintaining these methylation patterns. Beyond DNA methylation, modifications to histone proteins, around which DNA is compactly wrapped, also contribute to this regulatory process. Histone modifications can influence how tightly DNA is packaged, controlling gene accessibility and expression. The interplay between DNA methylation and histone modifications occurs at Imprinting Control Regions (ICRs), ensuring correct parent-of-origin specific expression.
Why Imprinting Matters
Gene imprinting is fundamental for normal mammalian development, particularly impacting fetal growth and placenta formation. Imprinted genes contribute to the delicate balance of nutrient transfer from the mother to the developing embryo, influencing both the growth rate and the overall size of the fetus. They also play a role in developing placental tissues, crucial for nutrient exchange. This regulation aligns with the “parental conflict hypothesis,” which suggests paternally expressed genes often promote fetal growth, while maternally expressed genes may act to restrain it, balancing resource allocation.
Beyond development, imprinted genes influence brain function, affecting behavior and cognition. Disruptions to imprinting patterns can have significant consequences, leading to developmental disorders and health issues. If an imprinted gene that should be active becomes silenced, or if a gene that should be silenced becomes active, the resulting imbalance in gene product dosage can be detrimental. Errors can result from genetic mutations, deletions, or abnormalities in the epigenetic machinery. Outcomes can range from growth abnormalities and metabolic dysfunction to neurological impairments.
Real-World Examples of Imprinting
Several well-characterized human conditions illustrate the clinical importance of correctly established gene imprints. Prader-Willi syndrome, for example, typically results from the absence or dysfunction of paternally expressed genes on chromosome 15. This can occur due to a paternal chromosome 15 deletion or inheriting two maternal copies (maternal uniparental disomy). Individuals with Prader-Willi syndrome often exhibit developmental delays, low muscle tone, and a persistent feeling of hunger leading to obesity.
Angelman syndrome, conversely, is also linked to the same region on chromosome 15 but arises when the maternally inherited copy of a specific gene, UBE3A, is either missing or mutated. This condition can also result from paternal uniparental disomy, where both copies of chromosome 15 are inherited from the father. Individuals with Angelman syndrome typically present with severe developmental delays, significant speech impairment, problems with balance and coordination, and a characteristically happy, excitable demeanor.
These two distinct syndromes, stemming from issues in the same genomic region but dependent on the parent of origin, underscore the critical role of imprinting. Another notable example is Beckwith-Wiedemann syndrome, which involves a cluster of imprinted genes on chromosome 11. This condition is frequently characterized by overgrowth, an enlarged tongue, abdominal wall defects, and an increased susceptibility to certain childhood cancers, stemming from an imbalance in the expression of paternally and maternally inherited genes in that region, such as IGF2 and CDKN1C.