The parent-of-origin effect is a genetic phenomenon where a gene’s expression depends entirely on whether it was inherited from the mother or the father. This means a child’s observable traits (phenotype) can be influenced differently by the exact same gene variant, based solely on which parent transmitted it. This mechanism challenges the conventional understanding of inheritance, where both copies of a gene are typically considered functionally equal. The effect suggests that certain genes maintain a memory of their parental source, which dictates their function.
Understanding the Difference in Inheritance
Standard Mendelian inheritance posits that an individual receives two copies, or alleles, of every gene, one from each biological parent, and that these two alleles function equivalently within the cell. For most genes in the human genome, a variation inherited from the mother will have the same effect as the identical variation inherited from the father. The expression level of the gene is determined by the combined activity of both copies.
The parent-of-origin effect represents a departure from this standard model, as it involves a small subset of genes where only one of the two inherited copies is functionally active. In these specific cases, the expression of the gene is monoallelic, meaning the copy from one parent is active while the copy from the other parent is effectively “silenced.” This silencing is not the result of a mutation in the DNA sequence but is instead a consequence of an epigenetic tag that the gene acquired during the formation of the egg or sperm. The sole determinant of whether a gene is active or inactive is its parental lineage.
The Mechanism of Genomic Imprinting
The molecular mechanism responsible for the parent-of-origin effect is genomic imprinting, an epigenetic process that marks specific genes for silencing without altering the underlying DNA sequence. This mechanism relies on chemical modifications to the DNA, most notably DNA methylation, which serves as the physical “imprint.” Methyl groups are attached to cytosine bases in DNA, typically within regions rich in cytosine and guanine nucleotides (CpG sites).
This methylation mark is established in the germline—the egg or sperm cells—of the parents before fertilization, and it determines which parental allele will be silenced in the offspring. For instance, a gene that is meant to be paternally expressed will have its maternal copy marked with methylation, leading to its inactivation. Conversely, a maternally expressed gene will have its paternal copy marked and silenced. These marks are concentrated in specialized regions called Imprinting Control Regions (ICRs), which act as genetic switches to regulate the expression of nearby imprinted genes.
The challenge of imprinting is that these parental marks must be maintained through all subsequent cell divisions in the developing embryo, even as the rest of the genome undergoes extensive reprogramming. Specialized enzymes, such as DNA methyltransferase 1 (DNMT1), are responsible for ensuring that the methylation pattern is accurately copied and maintained on the silent allele during cell replication.
The imprints are erased and reset in the germline of the next generation, ensuring that the new individual establishes imprints appropriate for their own sex before passing them on to their children. A male, for example, will erase the maternal and paternal imprints he received and establish new paternal imprints on all his sperm cells.
Specific Human Conditions Linked to Imprinting
Disruptions to the precise regulation of genomic imprinting can lead to distinct human disorders, offering clear evidence of the parent-of-origin effect in action. Two well-known examples, Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), involve the same small region on chromosome 15 (15q11-q13). Despite the shared location, the clinical outcome depends entirely on which parental copy of the chromosome is affected.
Prader-Willi Syndrome results from the loss of function of the paternally inherited genes in this region. Since the maternal copies of these genes are normally silenced by imprinting, the loss of the functional paternal copies leaves the individual with no active gene product. This leads to symptoms like poor muscle tone in infancy and later-onset excessive appetite. The syndrome can be caused by a deletion of the paternal segment, or by a phenomenon called uniparental disomy, where both copies of chromosome 15 are inherited from the mother.
In contrast, Angelman Syndrome results from the loss of function of the maternally inherited genes within the same 15q11-q13 region, most notably the UBE3A gene. The paternal copy of UBE3A is normally silenced, so if the functional maternal copy is deleted or mutated, the resulting lack of active protein causes the disorder. This leads to a distinct set of symptoms, including severe intellectual disability, movement difficulties, and frequent, unprovoked laughter.
The Evolutionary Theory Behind Imprinting
The existence of genomic imprinting, a complex mechanism that leaves an individual vulnerable to a single non-functional allele, prompts questions about its evolutionary purpose. The leading explanation is the “parental conflict hypothesis,” which suggests imprinting evolved due to differing evolutionary interests between the mother and the father regarding the allocation of maternal resources to the offspring. This theory is rooted in the concept of relatedness asymmetry, particularly in species where a female may mate with multiple males.
Paternal genes are predicted to evolve mechanisms that maximize the growth and resource acquisition of their offspring, even if it is costly to the mother’s health or her ability to bear future offspring with different fathers. This aggressive strategy is promoted because the paternal allele is only related to the current offspring and potentially a few others. Consequently, many paternally expressed genes are associated with enhanced fetal and placental growth.
Conversely, maternal genes are selected to conserve the mother’s resources, balancing the current offspring’s needs with the mother’s survival and her potential to produce future litters, which are all related to the mother. Therefore, maternally expressed genes often function as growth suppressors or modulators, regulating the amount of resources transferred from mother to fetus. This evolutionary tug-of-war between the paternal drive for aggressive growth and the maternal pressure for resource restraint provides the theoretical framework for why this intricate system of parent-specific gene silencing evolved.