Week 2 - P2 - L4 - Genomic Imprinting and Mitochondrial Inheritance Study of Cytoplasmic Inheritance

Genomic imprinting, also known as parental imprinting, is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner.
Under normal Mendelian inheritance, both alleles inherited from the parents are expressed. However, in genomic imprinting, one of the alleles is transcriptionally inactive, meaning no mRNA is produced, depending on which parent the allele was received from.
This process is conceptually similar to X-inactivation in XX individuals (where one X chromosome is silenced), but genomic imprinting specifically occurs on one gene located on an autosome.
The process of silencing a gene is formally referred to as imprinting. A transcriptionally silenced gene is said to be "imprinted."

Imprinted alleles are typically characterized by two primary epigenetic modifications:
- Heavy methylation: A chemical modification that often leads to reduced gene expression.
- Modifications in chromatin of specific histone types.
Epigenetics refers to changes in the structure surrounding the DNA that result in an increase or decrease in gene expression, without changing the actual DNA sequence itself.
In the context of imprinting, heavy methylation leads to the structural silencing of the DNA sequence.
This selective gene silencing impacts the phenotypic expression of an individual.
The silencing depends entirely on the parental origin of the genes and occurs during early development.

Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) provide classic examples of genomic imprinting in humans.
Both conditions are caused by a deletion in a specific region of chromosome 15, specifically the chromosomal regions $15q11$ to $q13$ .
The specific syndrome that develops depends on which parent provided the chromosome with the deletion.

Inheritance: Occurs if the deletion is inherited from the father.
Reasoning: Normally, at this specific site on the paternal chromosome, the genes $SNRPN$ and $NDN$ are active (expressed). If the paternal region is deleted, these genes are not expressed because the maternal copies of these specific genes are naturally silenced (imprinted).
Phenotypic Symptoms:
- An insatiable appetite leading to obesity.
- Development of Type 2 diabetes.
- Intellectual impairment and various learning disabilities.

Inheritance: Occurs if the deletion is inherited from the mother.
Reasoning: In this region, the gene $UBE3A$ is normally maternally expressed. If the maternal version is deleted, the individual has no active copy of $UBE3A$ because the paternal version is naturally silenced (imprinted).
Phenotypic Symptoms:
- Impacts the nervous system.
- Delayed development and intellectual disability.
- Severe speech impairment.
- Recurrent seizures in most affected children.
- A characteristic happy, excitable demeanor.

The region on chromosome 15 contains both paternally expressed genes and maternally expressed genes:
- PWS Region (paternally expressed): Active when inherited from the father; inactive/silenced when inherited from the mother.
- Angelman Syndrome gene ( $UBE3A$ ): Inactive/silenced when inherited from the father; active when inherited from the mother.
Scenario A (Father's side deleted): If the active PWS region from the father is deleted, the individual is left with only the maternal version, which is already silenced. This results in Prader-Willi Syndrome.
Scenario B (Mother's side deleted): If the active AS gene from the mother is deleted, the individual is left with only the paternal version, which is already silenced. This results in Angelman Syndrome.
While normally imprinting affects only single genes, this chromosome 15 region is unique because it contains both paternally and maternally imprinted genes within the same deleted segment.
Important Note: These conditions affect both males and females equally; the sex of the offspring does not determine the syndrome, only the sex of the parent providing the deleted chromosome.

Cytoplasmic inheritance refers to the inheritance of parental characteristics through non-chromosomal DNA.
In humans, the only source of non-chromosomal DNA is the mitochondria. In plants, this includes both mitochondrial DNA ( $mtDNA$ ) and chloroplast DNA.
Mitochondrial DNA is cytoplasmically inherited because the genetic information is not segregated during mitosis.
During conception, the sperm does not provide any mitochondria to the zygote; all mitochondria are derived from the female parent's egg.
Pattern of Inheritance: Matrilineal only. It may initially appear to be autosomal dominant because it affects both sexes, but closer inspection of pedigrees reveals the maternal link.

Size: The human mitochondrial genome is relatively small, consisting of approximately $16.5\,kb$ (kilobases).
Gene Count: It encodes exactly $37$ genes, which are essential for mitochondrial development and function.
Function: Mitochondria are responsible for energy production (ATP) and possess their own unique DNA.
Mutation Rate: Mitochondrial DNA has a high mutation rate compared to nuclear DNA.
Haplotypes and Tracking: Because blocks of genes are inherited together frequently, scientists use mitochondrial haplotypes to track individual lineages back through history and identify when specific mutations occurred over thousands of years within maternal lines.

Mitochondrial diseases are categorized by the distribution of the mutation within the cell's mitochondrial population.
- Homoplasmy: Every single mitochondrial genome within a cell or individual carries the causative variant (mutation).
- Heteroplasmy: The cell contains a mixed population of both normal (wild-type) and variant (mutated) mitochondrial genomes.
Segregation: Mitochondria segregate randomly during cell division. This random distribution can result in daughter cells that are heteroplasmic or, eventually, homoplasmic for either the normal or mutated genome.

Key Indicators:
- An affected female passes the condition to all of her children (both male and female).
- An affected male does not pass the condition to any of his children.
Comparison to Autosomal Dominant: While both can affect every generation and both sexes, autosomal dominant inheritance would typically show a $50\%$ transmission rate from an affected parent regardless of sex. Mitochondrial inheritance is distinguished by the total lack of transmission from affected males.

Explain the mechanism of complementary gene action.
Describe epistasis and related phenomena like the Bombay phenotype.
Explain how gene duplication impacts inheritance patterns.
Describe the interaction between genes and the environment with specific examples.
Understand the concepts of genomic imprinting, sex-influenced traits, and sex-limited traits.
Identify and analyze pedigrees affected by mitochondrial DNA mutations.