Nonclassical Patterns of Inheritance: Mitochondrial Inheritance, Genomic Imprinting, and Uniparental Disomy

Nonclassical Patterns of Inheritance

Overview

Nonclassical patterns of inheritance refer to genetic transmission mechanisms that deviate from traditional Mendelian inheritance. This study guide covers mitochondrial inheritance, genomic imprinting, and uniparental disomy/isodisomy, with emphasis on their molecular basis, clinical implications, and associated syndromes.

Mitochondrial Inheritance

Structure and Function of Mitochondria

• Mitochondria are organelles responsible for cellular energy production via oxidative phosphorylation (OXPHOS).

• Each cell contains hundreds to thousands of mitochondria, with numbers varying by tissue type.

• Mitochondria have their own genome (mtDNA), but most mitochondrial proteins are encoded by nuclear DNA.

The Mitochondrial Genome (mtDNA)

• Human mtDNA is a circular molecule, present in multiple copies per mitochondrion.

• Encodes 37 genes: 13 protein subunits (OXPHOS), 22 tRNAs, and 2 rRNAs.

• Genes are distributed between heavy and light strands.

Gene Type	Number
Protein subunits (OXPHOS)	13
tRNA	22
rRNA	2

Maternal Inheritance

• mtDNA is inherited exclusively from the mother, as sperm mitochondria are typically not transmitted to offspring.

• All mitochondria in the embryo originate from the oocyte.

Replicative Segregation

• Mitochondria and their genomes are randomly distributed to daughter cells during cell division.

• This process can lead to variation in the proportion of mutant and wild-type mtDNA in different cells and tissues.

Homoplasmy and Heteroplasmy

• Homoplasmy: All mitochondria in a cell/tissue have identical mtDNA (either all wild-type or all mutant).

• Heteroplasmy: A mixture of wild-type and mutant mtDNA within a cell/tissue. The proportion of mutant mtDNA influences disease severity.

Bottleneck Effect

• During oocyte maturation, the number of mitochondria is reduced to a small pool, then expands in the mature egg.

• This bottleneck can alter the ratio of mutant to wild-type mtDNA in offspring.

Threshold Effect

• Many mtDNA mutations are heteroplasmic; disease manifests only when the proportion of mutant mtDNA exceeds a critical threshold.

• Different tissues may have different thresholds for dysfunction.

Mitochondrial Diseases

• Caused by mutations in mtDNA or nuclear genes encoding mitochondrial proteins.

• Symptoms vary widely and may affect multiple organ systems, especially those with high energy requirements (e.g., brain, muscle).

• Examples: Leber Hereditary Optic Neuropathy (LHON), mitochondrial myopathies.

Leber Hereditary Optic Neuropathy (LHON)

• Characterized by rapid loss of central vision due to optic nerve degeneration.

• Most common mitochondrial disease; associated with specific mtDNA mutations.

• Penetrance and severity can vary due to heteroplasmy and other factors.

Genomic Imprinting

Definition and Mechanism

• Genomic imprinting is an epigenetic phenomenon where gene expression depends on the parent of origin.

• Imprinted genes are silenced via DNA methylation and histone modifications, often regulated by imprinting control regions (ICRs).

• Imprinting marks are reset during gametogenesis and re-established in the next generation.

Parental Conflict Theory

• Suggests imprinting evolved due to differing parental interests in resource allocation to offspring.

• Paternally expressed genes may promote growth; maternally expressed genes may restrict growth.

Human Imprinted Genes

• Approximately 150 human genes are imprinted.

• Imprinted genes are often clustered in specific chromosomal regions (e.g., 15q11-q13).

Examples: Prader-Willi and Angelman Syndromes

• Both syndromes involve deletions or mutations in the 15q11-q13 region, but differ in parent of origin.

• Prader-Willi Syndrome (PWS): Deletion on paternal chromosome 15; symptoms include developmental delay, obesity, and hypotonia.

• Angelman Syndrome (AS): Deletion on maternal chromosome 15; symptoms include severe intellectual disability, movement disorders, and happy disposition.

Syndrome	Chromosome Affected	Parent of Origin	Key Symptoms
Prader-Willi	15q11-q13	Paternal	Obesity, hypotonia, developmental delay
Angelman	15q11-q13	Maternal	Severe intellectual disability, movement disorder

Imprinting Control Region (ICR)

• ICRs are cis-acting elements that regulate the expression of imprinted genes via methylation and interaction with non-coding RNAs (lncRNAs).

• ICRs are methylated differently on maternal and paternal chromosomes.

Uniparental Disomy/Isodisomy

Definition

• Uniparental disomy (UPD): Both homologs of a chromosome are inherited from one parent.

• Isodisomy: Two identical copies of a single homolog from one parent.

• UPD can affect imprinted gene expression and contribute to disorders such as PWS and AS.

Summary Table: Nonclassical Inheritance Mechanisms

Mechanism	Key Features	Associated Disorders
Mitochondrial Inheritance	Maternal transmission, heteroplasmy, threshold effect	LHON, mitochondrial myopathies
Genomic Imprinting	Parent-of-origin gene expression, epigenetic regulation	PWS, AS
Uniparental Disomy	Both chromosomes from one parent	PWS, AS, other imprinting disorders

Key Equations and Concepts

• Threshold Effect Equation: Disease manifests when proportion of mutant mtDNA exceeds threshold $T$:

$\text{Disease if:} \quad \frac{\text{mutant mtDNA}}{\text{total mtDNA}} > T$

• Replicative Segregation: Random distribution of mitochondria during cell division leads to variable mutant load in daughter cells.

Clinical Applications

• Diagnosis of mitochondrial diseases involves genetic testing, biochemical assays, and pedigree analysis.

• Understanding imprinting is crucial for genetic counseling in families affected by PWS, AS, and other imprinting disorders.

Additional info:

• Imprinting and mitochondrial inheritance are important in assisted reproductive technologies and genetic counseling.

• UPD can result from errors in meiosis or post-zygotic events.