What is Dr. Zubair Khalid's research focus?

Dr. Zubair Khalid specializes in molecular virology, mRNA vaccine development, and computational biology, with a focus on avian pathogens like IBDV and Avian Reovirus.

Where is Dr. Zubair Khalid currently working?

Dr. Zubair Khalid is a Postdoctoral Research Associate at the University of Maryland (UMD), specifically within the Department of Animal and Avian Sciences.

Genomic Imprinting: Definition, Mechanism, and Examples

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-08-11

Introduction to Genomic Imprinting

What is genomic imprinting?

Genomic imprinting is an epigenetic phenomenon in which a subset of genes is expressed in a parent-of-origin-specific manner. In diploid organisms, most autosomal genes are expressed from both the maternal and paternal alleles. For imprinted genes, however, only one allele is transcriptionally active, and the other is silenced based on which parent contributed it. For example, the gene IGF2 (insulin-like growth factor 2) is expressed exclusively from the paternal allele in most tissues, while the maternal allele is silent. This means that the two alleles of an imprinted gene are functionally non-equivalent, despite having identical DNA sequences.

The molecular basis of imprinting lies not in changes to the DNA sequence itself but in chemical modifications—primarily DNA methylation and histone modifications—that are laid down differentially in the male and female germlines. These marks are heritable through somatic cell divisions, meaning that once an allele is silenced in the embryo, that silencing is faithfully propagated to all daughter cells. This places genomic imprinting squarely within the field of Epigenetic Inheritance, as the marks are passed from parent to offspring and maintained across cell generations.

Imprinting is distinct from other forms of monoallelic expression. X-chromosome inactivation silences an entire chromosome in females, whereas imprinting targets individual genes or clusters of genes on autosomes. It is also distinct from allelic exclusion in the immune system, where monoallelic expression is stochastic and cell-type-specific rather than parent-of-origin-determined.

Why is imprinting important?

Imprinting is important for several reasons. First, it violates the classical Mendelian expectation that maternal and paternal alleles contribute equally to the phenotype. A mutation in an imprinted gene can therefore produce a phenotype only when inherited from the parent whose allele is normally active. This creates non-Mendelian inheritance patterns that are clinically significant.

Second, imprinted genes are disproportionately involved in embryonic growth, placental development, and neurobehavioral processes. Many imprinted genes encode growth factors, growth factor receptors, or cell-cycle regulators. Disruptions in imprinting are associated with developmental disorders, including Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome, as well as with several cancers.

Third, imprinting provides a window into the evolutionary dynamics between maternal and paternal genomes. The parental conflict hypothesis, discussed later, posits that imprinting evolved because maternal and paternal interests in offspring resource allocation differ. Understanding imprinting therefore illuminates fundamental principles of gene regulation, development, and evolution.

The Mechanism of Genomic Imprinting

DNA methylation and histone modifications

The primary molecular mark that distinguishes the parental alleles of an imprinted gene is DNA methylation at cytosine residues within CpG dinucleotides. DNA methyltransferases (DNMTs) catalyze the transfer of a methyl group from S-adenosylmethionine to the 5-position of cytosine, producing 5-methylcytosine. In mammals, the maintenance methyltransferase DNMT1 recognizes hemimethylated CpG sites during DNA replication and methylates the newly synthesized strand, ensuring that methylation patterns are faithfully copied to daughter cells.

Two classes of DNA methyltransferases are relevant to imprinting. De novo methyltransferases DNMT3A and DNMT3B establish new methylation patterns during germ cell development, while DNMT1 maintains them during somatic cell divisions. DNMT3L, a catalytically inactive accessory protein, is required for de novo methylation in germ cells, particularly at imprinted loci.

Histone modifications also contribute to imprinting. The silenced allele of an imprinted gene typically carries histone H3 lysine 9 dimethylation (H3K9me2) and H3 lysine 27 trimethylation (H3K27me3), both associated with transcriptionally repressive chromatin. The active allele, in contrast, is enriched for histone H3 lysine 4 methylation (H3K4me3), a mark of active promoters. These histone marks are established and read by chromatin-modifying complexes, including the Polycomb repressive complex 2 (PRC2) for H3K27me3 and the G9a/GLP complex for H3K9me2. The interplay between DNA methylation and histone modifications is an example of Chromatin Remodeling that stabilizes the imprinted state.

Imprinting control regions (ICRs)

Imprinting is not distributed uniformly across the genome but is organized into clusters, each under the control of a cis-acting regulatory element called an imprinting control region (ICR). An ICR is a stretch of DNA, typically 2–5 kb in length, that is differentially methylated on the maternal and paternal alleles. These differentially methylated regions (DMRs) act as switchboards that coordinate the expression of multiple imprinted genes within a cluster.

ICRs function through two principal mechanisms: insulator-mediated silencing and non-coding RNA-mediated silencing.

In the insulator mechanism, an unmethylated ICR binds the zinc-finger protein CTCF (CCCTC-binding factor). CTCF binding creates a chromatin boundary that blocks the interaction between a distal enhancer and a promoter. When the ICR is methylated, CTCF cannot bind, and the enhancer is free to activate the promoter. The classic example is the IGF2/H19 locus on human chromosome 11p15.5, described in detail below.

In the non-coding RNA mechanism, the ICR contains a promoter for a long non-coding RNA (lncRNA). When the ICR is unmethylated, the lncRNA is transcribed through the cluster, and its transcription interferes with the expression of neighboring protein-coding genes, often by recruiting repressive chromatin modifiers. When the ICR is methylated, the lncRNA promoter is silenced, allowing the protein-coding genes to be expressed. The KCNQ1 and SNURF/SNRPN clusters use this mechanism.

The imprinting cycle in germ cells

Imprinting marks are not permanent across generations. They are erased in the primordial germ cells (PGCs) of the developing embryo and re-established according to the sex of the individual. This cycle ensures that a male passes on a paternally imprinted pattern and a female passes on a maternally imprinted pattern, regardless of the pattern they themselves inherited.

The imprinting cycle proceeds through three phases:

Erasure: Around embryonic day 10.5–12.5 in the mouse (corresponding to weeks 5–7 in human development), PGCs migrate into the developing gonads. At this stage, genome-wide demethylation occurs, including at imprinted loci. This involves both passive demethylation (failure to maintain methylation during replication) and active demethylation mediated by TET (ten-eleven translocation) enzymes, which oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized derivatives, ultimately leading to base excision repair and replacement with unmethylated cytosine. By the time PGCs enter the gonads, imprinted DMRs are largely unmethylated.

Establishment: After the PGCs arrive in the gonad, they undergo sex-specific differentiation. In the male germline, prospermatogonia enter mitotic arrest, and de novo methylation is established before birth. In the female germline, oocytes arrest in prophase I of meiosis, and de novo methylation occurs postnatally during oocyte growth, just before ovulation. DNMT3A and DNMT3L are the key enzymes, and the process is asynchronous: different imprinted loci acquire methylation at different times during oocyte development. The result is that sperm carry paternally methylated ICRs, and oocytes carry maternally methylated ICRs.

Maintenance: After fertilization, the zygote undergoes dramatic demethylation—the paternal genome is actively demethylated within hours, and the maternal genome is passively demethylated over subsequent cleavage divisions. However, imprinted DMRs are protected from this wave of demethylation. The zinc-finger protein ZFP57, together with the co-factor KAP1, binds to methylated ICRs and recruits DNMT1, maintaining methylation through the preimplantation period. This protection is essential; without ZFP57, imprinted marks are lost and development fails.

The erasure and re-establishment of imprinting marks is a critical distinction from most other epigenetic modifications, which are maintained throughout life. This cycle is a defining feature of Genetic Imprinting and is essential for producing gametes with the correct parent-of-origin information.

Imprinted Genes and Their Functions

IGF2 and H19

The IGF2/H19 locus is the best-characterized imprinted gene cluster and serves as the paradigm for understanding insulator-mediated imprinting. It is located on human chromosome 11p15.5 and contains two imprinted genes: IGF2, encoding insulin-like growth factor 2, and H19, encoding a long non-coding RNA.

IGF2 is expressed from the paternal allele, and H19 is expressed from the maternal allele. Both genes share a set of enhancers located downstream of H19. The key regulatory element is the H19 ICR (also called the imprinting control region or differentially methylated region), located between the two genes.

The mechanism is as follows:

On the maternal chromosome, the ICR is unmethylated. CTCF binds to the ICR, forming a chromatin boundary that blocks the enhancers from interacting with the IGF2 promoter. The enhancers therefore activate the H19 promoter, and H19 is transcribed. IGF2 remains silent.

On the paternal chromosome, the ICR is methylated. CTCF cannot bind. The boundary is absent, and the enhancers interact with the IGF2 promoter, driving its expression. The H19 promoter is methylated and silent.

IGF2 is a potent fetal growth factor. Mice with a paternal deletion of IGF2 are 40% smaller than wild-type littermates, demonstrating the importance of this gene in growth. Conversely, H19 RNA has growth-suppressive functions, and its loss leads to overgrowth. The reciprocal expression of these two genes ensures a balance between growth promotion and growth suppression.

CDKN1C and Beckwith-Wiedemann syndrome

CDKN1C (cyclin-dependent kinase inhibitor 1C), located in the same 11p15.5 cluster, encodes p57^KIP2^, a cyclin-dependent kinase inhibitor that negatively regulates the cell cycle. CDKN1C is expressed from the maternal allele only. Loss of maternal CDKN1C expression—through mutation, loss of heterozygosity, or loss of maternal methylation at the KCNQ1 ICR—causes Beckwith-Wiedemann syndrome (BWS).

BWS is characterized by macrosomia (excessive growth), macroglossia (enlarged tongue), abdominal wall defects (omphalocele), hemihyperplasia (asymmetric overgrowth), and an increased risk of embryonal tumors, particularly Wilms tumor and hepatoblastoma. The syndrome illustrates how a single imprinted gene can have profound effects on development and cancer predisposition.

The KCNQ1 ICR, located within intron 10 of the KCNQ1 gene, is unmethylated on the maternal allele. This unmethylated ICR acts as a promoter for the lncRNA KCNQ1OT1, which is transcribed in the antisense direction and silences CDKN1C in cis. On the paternal allele, the ICR is methylated, KCNQ1OT1 is not transcribed, and CDKN1C is expressed. Loss of maternal methylation at this ICR leads to biallelic KCNQ1OT1 expression and silencing of both CDKN1C alleles, producing BWS.

Other imprinted gene clusters

Several other imprinted clusters are clinically and biologically important:

**The SNURF/SNRPN cluster on 15q11-q13**: This cluster contains multiple imprinted genes, including SNRPN (encoding a spliceosomal protein), NDN (encoding necdin), and MAGEL2. It is regulated by a bipartite imprinting center. Paternal deletion or maternal uniparental disomy of this region causes Prader-Willi syndrome; maternal deletion or paternal uniparental disomy causes Angelman syndrome (detailed in the disease section).

**The DLK1/MEG3 cluster on 14q32**: Contains the paternally expressed DLK1 (delta-like homolog 1) and the maternally expressed lncRNA MEG3. Imprinting defects here cause Temple syndrome (maternal uniparental disomy of chromosome 14) and Kagami-Ogata syndrome (paternal uniparental disomy).

**The GRB10 gene on 7p12**: GRB10 is imprinted in a tissue-specific manner—paternally expressed in the brain but maternally expressed in most other tissues. This illustrates that imprinting is not always uniform across tissues.

**The GNAS complex locus on 20q13**: Contains several imprinted transcripts, including GNAS (encoding the G-protein alpha subunit), NESP55, and XLαs. Mutations or imprinting defects cause pseudohypoparathyroidism types 1A and 1B.

How Genomic Imprinting is Studied

Genetic crosses and allele-specific expression

The classical approach to identifying imprinted genes is to perform reciprocal crosses between two genetically distinct strains or species and then examine allele-specific expression in the offspring. If a gene is imprinted, the allele from one parent will be expressed and the other silenced, regardless of the genetic background.

In mice, this is typically done by crossing two inbred strains (e.g., Mus musculus domesticus and Mus spretus) that differ at many single-nucleotide polymorphisms (SNPs). RNA is extracted from F1 hybrid offspring, and the relative abundance of each parental allele is quantified by RT-PCR followed by sequencing or by using allele-specific primer extension assays. A gene is classified as imprinted if expression is skewed significantly toward one parental allele.

A complementary approach is to use uniparental embryos. In mice, gynogenetic embryos (containing two maternal genomes) and androgenetic embryos (containing two paternal genomes) can be constructed by pronuclear transfer. These embryos fail to develop normally—gynogenetic embryos have poor extraembryonic tissue, and androgenetic embryos have poor embryonic tissue—but they are useful for identifying imprinted genes by comparing expression between the two types.

Bisulfite sequencing and methylation analysis

Bisulfite sequencing is the gold standard for determining DNA methylation status at imprinted DMRs. Treatment of genomic DNA with sodium bisulfite converts unmethylated cytosines to uracil, while methylated cytosines remain unchanged. After PCR amplification and sequencing, the presence of cytosine indicates methylation, and the presence of thymine (from uracil) indicates unmethylated cytosines.

The typical bisulfite conversion protocol uses 3–5 M sodium bisulfite at pH 5.0, incubated at 50–55°C for 4–16 hours. After desulfonation and purification, the DNA is amplified with primers specific to bisulfite-converted DNA. The PCR products can be cloned and sequenced to determine the methylation status of individual molecules, or analyzed by pyrosequencing for quantitative methylation levels at specific CpG sites.

For high-throughput analysis, bisulfite-converted DNA can be hybridized to methylation arrays (e.g., Illumina Infinium MethylationEPIC BeadChip, which covers over 850,000 CpG sites) or subjected to whole-genome bisulfite sequencing. These approaches allow genome-wide identification of DMRs between parental alleles.

Genomic imprinting databases

Several databases catalog imprinted genes and their regulatory features:

Geneimprint (geneimprint.org): A curated database of imprinted genes in humans and mice, with information on tissue-specific expression and imprinting status.

Wamid (Watson Imprinting Database): A database of imprinted genes in the mouse, with links to expression data.

The Imprinting Center at the University of Otago: Provides a comprehensive list of imprinted genes, DMRs, and associated diseases.

The NCBI Imprinting Resource: Integrates imprinting data with genomic annotations.

These databases are valuable for cross-referencing experimental results and for identifying candidate imprinted genes in genomic regions of interest.

Evolutionary Significance of Imprinting

The kinship theory

The most widely accepted explanation for the evolution of genomic imprinting is the kinship theory, also known as the parental conflict hypothesis, proposed by David Haig in the late 1980s. The theory argues that imprinting evolved because maternal and paternal genomes have different interests in the allocation of maternal resources to offspring.

Consider a paternally expressed growth promoter like IGF2. A father's evolutionary fitness is maximized by having his offspring extract as many resources as possible from the mother, even at the cost of the mother's future reproduction. This is because the father's genes are present in the current offspring but not necessarily in the mother's future offspring (which may be sired by a different male). A mother's fitness, in contrast, is maximized by distributing resources equally among all her offspring, both current and future. The mother's genes are present in all her offspring, regardless of paternity.

The theory predicts that paternally expressed genes will promote growth and resource extraction, while maternally expressed genes will restrain growth. This prediction is borne out by the data: most paternally expressed imprinted genes promote growth (e.g., IGF2, DLK1, PEG3), and most maternally expressed imprinted genes suppress growth (e.g., H19, CDKN1C, GRB10). The reciprocal expression of IGF2 and H19 is a textbook example of this conflict.

The kinship theory also makes predictions about tissue-specific imprinting. In the placenta, where resource transfer occurs, imprinting should be particularly important. Indeed, many imprinted genes are highly expressed in the placenta, and some are imprinted only there. In the brain, the conflict may manifest differently, as genes expressed in the brain can influence behavior toward siblings and other relatives. This may explain the enrichment of imprinted genes in the brain and their involvement in social behavior.

Imprinting in placental mammals

Imprinting is not universal among animals. It has been found in placental mammals (eutherians) and, to a lesser extent, in marsupials, but not in monotremes (egg-laying mammals), birds, fish, or reptiles. This phylogenetic distribution is consistent with the kinship theory: imprinting evolved in lineages where the fetus is nourished directly by the mother through a placenta, creating the potential for conflict over maternal resource allocation.

In marsupials, which have a short placental gestation followed by extended lactation, imprinting is less extensive than in eutherians. Some imprinted genes, such as IGF2 and H19, are imprinted in marsupials, but others are not. This suggests that imprinting evolved in a gene-by-gene manner, with the earliest imprinted genes being those most directly involved in placental growth.

The evolution of imprinting required the co-option of existing epigenetic machinery. DNA methylation, histone modifications, and CTCF binding all predate imprinting. What evolved was the targeting of these mechanisms to specific loci in a parent-of-origin-specific manner, likely through the acquisition of novel regulatory elements (ICRs) and the recruitment of germline-specific methylation factors.

Genomic Imprinting in Disease

Uniparental disomy

Uniparental disomy (UPD) is a condition in which an individual inherits both copies of a chromosome from one parent and none from the other. UPD can arise through errors in meiosis or mitosis, often through trisomy rescue (loss of one chromosome from a trisomic conceptus) or gamete complementation (fertilization of a gamete with a chromosomal abnormality by a gamete with the complementary abnormality).

UPD causes disease when the affected chromosome carries imprinted genes. For example:

Maternal UPD 15 (both copies of chromosome 15 from the mother) causes Prader-Willi syndrome because the paternally expressed genes in the 15q11-q13 region (e.g., SNRPN, NDN) have no active copy.

Paternal UPD 15 causes Angelman syndrome because the maternally expressed gene UBE3A (ubiquitin-protein ligase E3A) has no active copy in the brain.

Maternal UPD 7 causes Silver-Russell syndrome, characterized by growth restriction, because of loss of paternally expressed growth-promoting genes on chromosome 7, including GRB10 and PEG10.

Paternal UPD 11 causes Beckwith-Wiedemann syndrome because of loss of maternally expressed growth suppressors such as CDKN1C.

UPD is diagnosed by microsatellite analysis or SNP arrays that can distinguish maternal and paternal alleles.

Imprinting center mutations

Some imprinting disorders are caused by mutations in the imprinting center (IC), a regulatory element that controls the establishment or maintenance of imprinting across an entire cluster. The best-characterized example is the 15q11-q13 IC, which is bipartite: the Prader-Willi syndrome IC (PWS-IC) and the Angelman syndrome IC (AS-IC) are adjacent but functionally distinct elements.

The PWS-IC is a ~4 kb region that includes the promoter and exon 1 of SNRPN. It is unmethylated on the paternal allele and methylated on the maternal allele. The AS-IC is located ~35 kb upstream and is required for the establishment of maternal methylation at the PWS-IC. Mutations in the AS-IC prevent maternal methylation from being established in the oocyte, leading to a paternal epigenotype on the maternal chromosome. This produces Angelman syndrome even when both chromosomes are inherited from both parents (biparental inheritance).

Microdeletions of the IC account for ~1–3% of Prader-Willi and Angelman syndrome cases. These deletions are often familial, with a 50% recurrence risk if inherited from the appropriate parent.

Cancer and imprinting

Imprinted genes are frequently dysregulated in cancer. Loss of imprinting (LOI) refers to the biallelic expression of a gene that is normally monoallelically expressed. LOI at the IGF2/H19 locus is one of the most common epigenetic alterations in human cancers, occurring in Wilms tumor, colorectal cancer, hepatocellular carcinoma, and many others.

In Wilms tumor, LOI of IGF2 results in a doubling of IGF2 expression, which promotes cell proliferation through the IGF1 receptor signaling pathway. The mechanism of LOI often involves loss of methylation at the H19 ICR on the paternal allele, leading to biallelic CTCF binding and silencing of IGF2 on both alleles—or, more commonly, gain of methylation on the maternal allele, leading to biallelic IGF2 expression.

Other imprinted genes implicated in cancer include CDKN1C (silenced in many tumors), ARHI (a maternally expressed tumor suppressor on chromosome 1p31, frequently silenced in breast and ovarian cancers), and PEG3 (a paternally expressed gene with pro-apoptotic functions, silenced in gliomas).

The reversible nature of imprinting marks makes them attractive therapeutic targets. Drugs that inhibit DNA methyltransferases, such as 5-azacytidine and decitabine, can reactivate silenced imprinted genes and are used clinically in myelodysplastic syndromes and acute myeloid leukemia.

Common Misconceptions and Pitfalls

Imprinting is not the same as X-inactivation

A common confusion is equating genomic imprinting with X-chromosome inactivation. Both involve monoallelic expression and epigenetic silencing, but they differ fundamentally:

X-inactivation silences an entire X chromosome in female mammals to achieve dosage compensation between XX females and XY males. It is random with respect to parental origin in the embryo proper (though imprinted in the extraembryonic tissues of rodents).

Imprinting targets specific autosomal genes and is deterministic—the parental origin of the allele determines its expression, not chance.

X-inactivation is a chromosome-wide phenomenon; imprinting is locus-specific. The molecular mechanisms also differ: X-inactivation is mediated by the lncRNA XIST and involves widespread H3K27me3 deposition, whereas imprinting is mediated by ICRs and involves DNA methylation at specific DMRs.

Imprinting marks are not always permanent

It is a misconception that an imprinted allele is silenced in every cell of the body for the entire lifetime of the organism. Imprinting can be:

Tissue-specific: Some genes are imprinted in the placenta but biallelically expressed in the embryo (e.g., IGF2R in mice). Others, like GRB10, show opposite imprinting patterns in different tissues.

Developmentally regulated: Imprinting can be established or lost during development. For example, IGF2 is biallelically expressed in the early embryo and becomes imprinted only after implantation.

Plastic: Imprinting marks can be lost in disease states, as in cancer, or in response to environmental factors.

The erasure of imprinting marks in the germline, described earlier, is another example of their non-permanence.

Not all imprinted genes are silenced

The term "imprinted gene" refers to a gene whose expression depends on parental origin, but this does not always mean complete silencing of one allele. Some imprinted genes show partial or quantitative differences in expression rather than all-or-none silencing. For example, UBE3A is imprinted only in specific neurons of the brain; in other tissues, it is biallelically expressed. Similarly, some imprinted genes show "leaky" expression from the silenced allele at low levels.

Additionally, some genes are imprinted in a polymorphic manner—imprinted in some individuals but not others, depending on genetic variants at the ICR. This complicates the simple binary view of imprinting.

Imprinting is not the same as gene silencing

While imprinting involves Gene Silencing of one allele, gene silencing is a broader concept that includes many other phenomena, such as transcriptional repression by repressor proteins, RNA interference, and heterochromatin formation. Imprinting is a specific form of allele-specific silencing that is parent-of-origin-dependent and established in the germline. Not all gene silencing is imprinted, and not all imprinted genes are completely silenced.

Imprinting is not a form of mutation

Imprinting is an epigenetic phenomenon—it does not involve changes to the DNA sequence. A student might mistakenly think that an imprinted allele has a different sequence from the active allele. In fact, the two alleles are sequence-identical; they differ only in their epigenetic marks. This is why imprinting can be reversed by nuclear transfer or by demethylating agents.

Summary and Key Takeaways

Genomic imprinting is a fascinating and clinically important example of epigenetic regulation. It demonstrates that inheritance is not solely a matter of DNA sequence but also of the modifications that accompany DNA through the germline.

Frequently Asked Questions

What does genomic imprinting mean?

Genomic imprinting means that a gene is expressed from only one parental allele, with the other allele silenced based on its parent of origin. The choice of which allele is active is determined by epigenetic marks—primarily DNA methylation—established in the sperm or egg.

What are the steps of genomic imprinting?

The steps are: (1) erasure of existing imprinting marks in primordial germ cells; (2) establishment of new marks in a sex-specific manner during gametogenesis (DNMT3A/DNMT3L-mediated methylation in oocytes or sperm); (3) maintenance of marks after fertilization through the preimplantation demethylation waves (ZFP57/KAP1-mediated protection); and (4) reading of the marks in somatic cells to produce allele-specific expression.

How would you define genomic imprinting?

Genomic imprinting is a parent-of-origin-specific form of gene regulation in which a subset of autosomal genes is expressed monoallelically, with the expressed allele determined by whether it was inherited from the mother or the father.

What is the process of genomic imprinting?

The process involves the differential methylation of imprinting control regions in the male and female germlines. These differentially methylated regions recruit or block the binding of regulatory proteins such as CTCF, or drive the expression of non-coding RNAs, resulting in the silencing of one parental allele in the offspring.

Can you give a summary of genomic imprinting?

Genomic imprinting is an epigenetic mechanism that causes monoallelic, parent-of-origin-specific expression of a subset of genes. It is established in the germline by DNA methylation, maintained in somatic cells, erased in the next generation's germline, and is important for growth, development, and behavior. Disruptions cause human diseases including Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes.

What is an example of genomic imprinting?

The IGF2/H19 locus is the classic example. IGF2 is expressed from the paternal allele and H19 from the maternal allele. The reciprocal expression is controlled by a differentially methylated region that binds CTCF on the maternal chromosome, blocking enhancer access to IGF2.

Why is genomic imprinting important in biology?

Imprinting is important because it (1) violates Mendelian expectations and creates non-Mendelian inheritance patterns; (2) regulates key developmental processes including fetal growth and placental function; (3) provides a model for understanding epigenetic inheritance; (4) is disrupted in numerous genetic disorders and cancers; and (5) offers insight into evolutionary conflicts between maternal and paternal genomes.

Key Takeaways

Genomic imprinting is parent-of-origin-specific monoallelic expression, controlled by epigenetic marks rather than DNA sequence.
DNA methylation at imprinting control regions is the primary mark, established in the germline by DNMT3A/DNMT3L and maintained in somatic cells by DNMT1.
Imprinting marks are erased in primordial germ cells and re-established according to sex, ensuring that each generation receives the correct parental pattern.
Imprinted genes are organized into clusters regulated by ICRs that act through CTCF-mediated insulation or non-coding RNA-mediated silencing.
Paternally expressed genes tend to promote growth; maternally expressed genes tend to restrain it, consistent with the kinship theory of imprinting evolution.
Imprinting defects cause Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and contribute to cancer.
Imprinting is not the same as X-inactivation, is not permanent across generations, and does not always result in complete silencing of one allele.