Comprehensive Notes on Genomic Imprinting and Epigenetic Inheritance

The Problem of Embryonic Viability: A fundamental biological question is why an embryo cannot be created simply by fusing $2$ eggs. One of the primary reasons this is not possible is the phenomenon of genomic imprinting.
The Requirement for Sexual Reproduction: Sexual reproduction necessitates genetic contributions (genes) from both sexes—a male and a female—to generate viable offspring.
Ensuring Biparental Contribution: Imprinting is a specialized process that ensures the genetic input from both the mother and the father is present and functional in the offspring.

Definition of Imprints: Imprints are marks on our chromosomes that distinguish which chromosomes were inherited from the egg (maternal chromosomes) and which were inherited from the sperm (paternal chromosomes).
Functional Regulation: These imprints regulate the expression of the imprinted gene. Specifically, the alleles of these genes are expressed according to their parent of origin.
Expression Patterns:
- Humans possess $2$ copies of every gene: one from the mother and one from the father.
- In an imprinted gene, one of these alleles is "imprinted" (silenced), and the other version is expressed.
Biochemical Mechanism (Methylation): Imprinted alleles are marked with methylated $CpG$ dinucleotides. This DNA methylation occurs at the promoter of the gene to effectively stop the expression of that specific allele.
The Silent Allele: The imprinted allele is defined as the version or copy of the gene that is not being expressed and is methylated.

Gene: A specific DNA sequence containing information used to manufacture a protein.
Allele: A version of a gene representing an actual DNA sequence.
- Sequence Differences: While alleles usually contain slight sequence differences, they typically produce the same protein functionality.
- Phenotypic Outcome: Sequence differences determine specific outcomes (phenotypes). For example, the gene for eye color is inherited as $2$ alleles ( $1$ from each parent). Both alleles produce the protein for eye color, but the sequence variations result in blue, brown, or green eyes.
Autosomal Genes: These are genes where an individual receives $1$ allele from the mother and $1$ allele from the father, often featuring slight sequence variations.
Epigenetic Modification: DNA methylation is an epigenetic modification. Because it is epigenetic, it does not change the DNA sequence itself and is reversible.

Gene Count: There are approximately $100$ genes in the human genome that undergo imprinting.
Population Consistency: Imprinting is consistent across all individuals; the same specific genes are maternally or paternally imprinted in every person.
Hypothetical Example (Gene $ABCD$ ):
- If Gene $ABCD$ is maternally imprinted, every person carries $2$ alleles ( $1$ maternal, $1$ paternal).
- In every person, the allele from the mother will be methylated (silenced), and the allele from the father will be expressed.
Adaptation to Monoallelic Expression: Our biological systems are specifically adapted to this level of expression. We only require $1$ copy of these imprinted genes to be expressed to provide sufficient protein for the necessary cellular functions.

Definition: In maternal imprinting, the gene is not expressed on the allele inherited from the mother. This is controlled by DNA methylation of the maternal $CpG$ island.
Pedigree Example:
- Consider a family with a mother (alleles $1$ , $2$ ) and a father (alleles $3$ , $4$ ).
- The son inherits allele $1$ from the mom and allele $4$ from the dad.
- Because the gene is maternally imprinted, allele $1$ is switched off (silenced/methylated), indicated by a lighter color and an "X" representing no $\text{RNA}$ production.
- The son expresses only allele $4$ .
- The daughter inherits allele $2$ from the mom and allele $3$ from the dad; allele $2$ is silenced, and allele $3$ is expressed.
General Rule: For maternally imprinted genes, everyone expresses only the allele inherited from their father.

Definition: In paternal imprinting, the allele inherited from the father is silenced and not expressed.
Pedigree Example:
- Using the same family (Mother: $1, 2$ ; Father: $3, 4$ ).
- The son inherits allele $4$ from the father; because it is paternally imprinted, allele $4$ is inactivated.
- The son expresses allele $1$ from the mother.
- The daughter inherits allele $3$ from the father; allele $3$ is inactivated, and she expresses allele $2$ from the mother.
General Rule: For paternally imprinted genes, everyone expresses only the allele inherited from their mother.
Distribution: Nearly every chromosome in the human genome contains both maternally and paternally imprinted genes.

The Inheritance Paradox: Consider a maternally imprinted gene. A son inherits an inactive allele from his mother. However, when that son becomes a father, his children rely on him to provide an active allele (since the children will silence the allele from their own mother).
The Solution - Reversibility: Because imprints are epigenetic, they can be reversed. This occurs during gametogenesis.
Wiping and Resetting:
- When an individual produces gametes (eggs or sperm), the existing imprints inherited from their own parents are completely wiped.
- There is no "memory" in the gamete of which allele came from which grandparent.
- The imprints are then re-established according to the biological sex of the individual.
Resetting in the Mother: In her eggs, all alleles for maternally imprinted genes will be methylated and inactivated, regardless of whether they were active in her own somatic cells.
Resetting in the Father: In his sperm, all imprints for maternally imprinted genes are cleared. Even if he inherited a silenced allele from his mother, he resets it so that it is active in his sperm. He only establishes paternal imprints.
Outcome for the Child: This process ensures that a child always receives a silenced allele from the mother (imprinted) and an active allele from the father (unimprinted) for maternally imprinted genes, maintaining the correct combination for development.

Question: How does Tutu (this individual in the pedigree) pass an active allele to his child if that allele is actually inactive in all of his cells?
Answer: This is achieved through the resetting of imprints during gametogenesis. The father's body wipes the maternal imprint he inherited and re-establishes imprints that match his own sex. Since he is male, he does not apply maternal imprints to his gametes, ensuring the allele he passes on is active and expressed in his offspring.

Parent-of-Origin: Imprinted genes are expressed based solely on which parent provided the allele.
Scale: There are roughly $100$ such genes across the human genome.
Gametogenesis: Imprints are reset during the creation of eggs and sperm to match the sex of the parent.
Monoallelic Sufficiency: All imprinted genes function normally with only $1$ active allele; this single dose provides the correct amount of protein for the cell.