Genomic imprinting is an exception to the standard rules of inheritance, where an individual typically receives two functional copies of every gene, one from each parent. Instead of both copies being active, imprinting is a biological process where a small subset of genes is expressed from only one of the two parental chromosomes. This phenomenon means that whether a gene is turned “on” or “off” depends entirely on whether it was inherited from the mother or the father. This unusual pattern of gene expression is fundamental to development and growth.
The Core Concept of Genomic Imprinting
Genomic imprinting functions through monoallelic expression, where only one of the two gene copies, or alleles, is active while the other remains silent. This silencing is achieved through epigenetic modifications—changes to the DNA and its associated proteins that do not alter the underlying genetic code. Chemical tags are added that act like an invisible switch, controlling whether the gene is read and translated into a protein.
The primary mechanism for this silencing is DNA methylation, which involves adding a methyl group tag to specific cytosine nucleotides in regions known as CpG islands. When these specific regions, often called Imprinting Control Regions (ICRs), are methylated, they prevent the cellular machinery from accessing and reading the gene, effectively turning it off. This methylation mark is established in the parent’s germline cells and maintained throughout the offspring’s life.
Beyond DNA methylation, other epigenetic tools like histone modification also regulate imprinting. Histones are the proteins that DNA wraps around to form chromatin. Chemical tags added to these histones can either tighten or loosen the DNA structure, making the DNA inaccessible and silencing the gene. While DNA methylation is the more stable mechanism, histone modifications are important in the very early stages of embryonic development.
Setting the Mark: How Maternal and Paternal Imprints Differ
The mark that determines which gene copy is silenced is set during the formation of the parent’s reproductive cells (gametes). This process occurs in a sex-specific manner, meaning the pattern of silenced genes is distinct in developing sperm compared to developing eggs. These marks are established at specific chromosomal regions, known as germline differentially methylated regions (gDMRs), which dictate the expression pattern after fertilization.
For certain imprinted genes, the copy inherited from the mother is silenced, meaning only the paternal copy is active in the offspring, such as with the IGF2 gene. Conversely, other imprinted genes are silenced only when inherited from the father, leaving the maternal copy as the sole active source of the protein. This differential marking ensures the embryo receives a functional dose of the gene from one parent while the copy from the other is suppressed.
A crucial feature of imprinting is its reversibility in the germline of the next generation. The original epigenetic mark is completely erased in the primordial germ cells, regardless of which parent the individual received the gene from. The DNA is then re-marked, or “re-imprinted,” according to the sex of that individual, ensuring the correct parent-of-origin expression pattern is passed to the offspring.
Evolutionary Theories Behind Parent-of-Origin Effects
The existence of genomic imprinting, which leaves only one functional copy of a gene, suggests strong evolutionary pressure. The most widely accepted explanation is the “Conflict Hypothesis,” also known as the kinship theory. This theory posits a genetic “tug-of-war” between the paternal and maternal genomes over the allocation of maternal resources to the offspring during pregnancy.
The father’s interest lies in promoting the robust growth of his current offspring, even if it demands greater maternal resources. The mother, however, benefits from conserving and distributing her resources among all her current and future offspring, who may be fathered by different males. This conflict leads to an asymmetry in gene expression: paternal genes tend to promote growth and resource extraction, while maternal genes tend to limit growth and conserve resources.
Specific genes provide evidence for this hypothesis, most notably the IGF2 gene, which promotes fetal growth and is expressed only from the paternally inherited copy. Conversely, the IGF2 receptor gene, IGF2R, which suppresses the growth effects of IGF2, is expressed only from the maternally inherited copy. This reciprocal imprinting pattern creates a delicate balance where the growth-promoting signal from the father is kept in check by the growth-limiting signal from the mother. The conflict hypothesis explains the observed patterns of imprinting in mammals, particularly for genes involved in placental development and nutrient acquisition.
Imprinting, Disease, and Human Health
Failure in genomic imprinting can lead to severe developmental disorders. A classic example involves a cluster of imprinted genes on human chromosome 15, associated with two distinct neurogenetic disorders: Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS). Both syndromes result from a deletion in the same 15q11-q13 chromosomal region, but the resulting condition depends entirely on which parent contributed the deleted chromosome.
PWS occurs when the deletion is inherited from the father, resulting in a loss of function of multiple paternally expressed genes. Symptoms include severe hypotonia in infancy, followed by an insatiable appetite leading to obesity. Conversely, AS results when the identical deletion is inherited from the mother, causing a loss of function of maternally expressed genes, including UBE3A. AS is characterized by severe intellectual disability and movement disorders.
Imprinting is also relevant to cancer through Loss of Imprinting (LOI). LOI is a failure to maintain the correct monoallelic expression pattern, often resulting in the abnormal activation of a normally silent gene copy. This misregulation can be an early event in tumor development. For instance, LOI at the IGF2-H19 locus is frequently observed in various cancers, such as Wilms tumor. The activation of the normally silent maternal copy of the growth-promoting IGF2 gene results in an increased protein dosage, fueling uncontrolled cell proliferation.