We inherit two copies of each gene, one from each parent. While both are typically active, genomic imprinting is an exception. This unique biological process dictates whether a gene is expressed or silenced based on its parental origin.
Understanding Genomic Imprinting
Genomic imprinting is an epigenetic phenomenon where certain genes are expressed or silenced depending on whether they were inherited from the mother or the father. Unlike typical Mendelian inheritance, where both copies of a gene are usually active, imprinted genes exhibit monoallelic expression. This means only one parent’s copy is active, while the other is silenced.
For example, if a gene is paternally imprinted, only the copy inherited from the mother will be active, and the paternal copy will be silenced. Conversely, if a gene is maternally imprinted, only the paternal copy will be expressed. These modifications are established during the formation of egg or sperm cells and are maintained throughout an individual’s life.
The Molecular Basis of Imprinting
Genomic imprinting operates through epigenetics, which are changes in gene expression that do not alter the DNA sequence itself but rather modify how the DNA is read. These modifications involve chemical tags added to the DNA or changes to the proteins that DNA wraps around. The primary epigenetic mechanisms involved in establishing and maintaining imprints are DNA methylation and histone modifications.
DNA methylation involves adding a chemical tag, a methyl group, to specific DNA building blocks called cytosine residues, often found in CpG dinucleotides. This methylation typically leads to gene silencing by making the DNA less accessible for transcription. In imprinted genes, this methylation is applied to one parental allele and remains stable after fertilization.
Histone modifications involve changes to histones, which are spool-like proteins around which DNA is tightly wound to form chromatin. These modifications, such as the addition of methyl or acetyl groups, can alter the chromatin structure, making genes either more accessible for expression or more tightly packed and silenced. Specific histone methylation patterns contribute to the parent-specific expression of imprinted genes, with some marks associated with active expression and others with repression.
These epigenetic marks are often found in specific regulatory regions known as Imprinting Control Regions (ICRs). ICRs are key DNA sequences that control the expression of one or more imprinted genes within a cluster. These regions acquire their parent-of-origin-specific epigenetic marks in the germline, ensuring that the correct parental allele is expressed or silenced in the offspring.
Imprinting’s Role in Development and Disease
Genomic imprinting plays a significant role in normal embryonic development and overall health after birth. The precise regulation of these imprinted genes is crucial for proper fetal growth and the development of various tissues and organs, including the brain. A small number of imprinted genes are involved in regulating fetal growth, with some promoting growth and others restricting it, highlighting a balance that is maintained through imprinting.
When genomic imprinting goes awry, it can lead to various human diseases and syndromes, often due to incorrect gene dosage. These disorders arise from errors in the establishment, maintenance, or erasure of imprints, or from genetic alterations in imprinted regions. Two well-known examples are Prader-Willi Syndrome and Angelman Syndrome, which are caused by issues within the same region of chromosome 15 (15q11-q13) but result in different sets of symptoms due to the parent-of-origin effect.
Prader-Willi Syndrome typically results from the absence of paternally expressed genes in the 15q11-q13 region, often due to a deletion on the paternal chromosome 15 or inheriting two copies of maternal chromosome 15 (uniparental disomy). This leads to symptoms such as weak muscles in infancy, poor feeding, and later, an insatiable appetite leading to obesity, along with intellectual impairment and behavioral problems.
Angelman Syndrome, in contrast, is caused by the loss of function of the maternally inherited UBE3A gene within the same chromosome 15q11-q13 region. This can occur due to deletions on the maternal chromosome, mutations in the UBE3A gene, or inheriting two paternal copies of chromosome 15. Individuals with Angelman Syndrome typically exhibit developmental delays, severe speech impairment, intellectual disability, movement and balance disorders, and characteristic episodes of laughter.