Chapter #6 Extranuclear Inheritance, Genomic Imprinting, and Maternal Effect

Chapter 6: Extranuclear Inheritance, Genomic Imprinting, and Maternal Effect

Introduction to Mendelian Inheritance

Simple Mendelian inheritance refers to inheritance patterns that adhere to two fundamental principles:

  • The Law of Segregation: This law posits that allele pairs separate or segregate during gamete formation and unite at random during fertilization.

  • The Law of Independent Assortment: Genes are transmitted independently of one another during the formation of gametes.
    In this model, genes are inherited unaltered from one generation to the next (excluding rare mutations), and the expression of these genes in offspring directly determines their traits. However, some genes can display behaviors that violate these Mendelian predictions.

Overview of Non-Mendelian Inheritance

Non-Mendelian inheritance encompasses a few fundamental categories:

  • Extranuclear Inheritance: This form refers to the inheritance of traits through genes located outside the nucleus, specifically within organelles such as mitochondria and chloroplasts.

  • Epigenetic Inheritance and Imprinting: Occurs when gene expression changes without altering the DNA sequence, such as through methylation.

  • Maternal Effect: This highlights gene expression in the mother influencing the traits of the offspring, irrespective of the father's genetic contribution.

Extranuclear Inheritance

Extranuclear inheritance is defined as the transmission of traits through genetic material located outside the nucleus, often in organelles like mitochondria and chloroplasts. It is also referred to as cytoplasmic inheritance and represents a clear violation of the Law of Segregation.

Chloroplast Genome

The genomic structure of both mitochondria and chloroplasts is characterized by:

  • A single circular double-stranded chromosome (DNA).

  • Similar to bacterial DNA, these organelle DNA types are present in structures known as nucleoids.

  • Nucleoids can house many copies of one chromosome and potentially multiple nucleoids, facilitating organelle replication and function.

Maternal Inheritance: Historical Context

In 1909, Carl Correns found that leaf pigmentation in certain plants could not be predicted by Mendelian genetics, establishing the concept of maternal inheritance. The phenotype observed was strictly dependent on the mother's genotype as the egg cell contributes the cytoplasm and organelles to the zygote, while the father's contribution lacks any cytoplasmic inheritance through pollen.

Variegated Phenotype in Mirabilis jalapa

The variegated phenotype seen in Mirabilis jalapa results from the way chloroplasts are distributed during mitosis. Unlike chromosomal inheritance where specific chromosomes segregate, chloroplasts are randomly assorted into daughter cells:

  • Some cells may contain only wild-type chloroplasts leading to green leaves.

  • Others may have all mutant chloroplasts resulting in white leaves.

  • Some cells can exhibit heteroplasmy with mixed types of chloroplasts appearing green due to the presence of functional chloroplast DNA.

Chloroplast Inheritance Patterns

In species that reproduce via distinct gametes:

  • Large egg cells usually carry most of the cytoplasm, leading to maternal inheritance of chloroplasts.

  • Some gymnosperms demonstrate paternal inheritance.

  • A few angiosperms exhibit biparental inheritance, although exceptions exist based on parental contribution and heteroplasmy events in the progeny.
    To predict an offspring's phenotype concerning extranuclear genes, knowing which parents transmit the gene as well as the presence of heteroplasmy is essential.

The Mitochondrial Genome

Similar to chloroplasts, mitochondria are characterized by:

  • A single circular chromosome contained within the nucleoid.

  • Multiple copies of this chromosome can exist within several nucleoids in one organelle.

Function of Mitochondria

The primary role of mitochondria encompasses:

  • Oxidative phosphorylation, which is crucial for producing ATP, the energy currency of the cell.

  • Human mitochondrial DNA (mtDNA) comprises about 17,000 base pairs, encoding relatively few genes, including rRNA and tRNA genes, as well as 13 genes encoding polypeptides essential for mitochondrial functions. Notably, most mitochondrial proteins are synthesized from nuclear DNA but require signals for localization to mitochondria.

Mitochondrial Inheritance Patterns

Typically, mitochondria are inherited maternally from the female parent across numerous species:

  • Mammals: Exhibit strict maternal inheritance patterns.

  • Saccharomyces cerevisiae (yeast): display biparental inheritance.

  • Molds: demonstrate mostly maternal inheritance but occasional paternal inheritance (e.g., in the genus Allomyces).

  • Chlamydomonas: inherit mitochondria from the parent with the mt+ mating type.

  • Plants: show varied patterns, with angiosperms typically inheriting through maternal lines but some exhibiting biparental traits, whereas gymnosperms show prevalent paternal inheritance.

Paternal Leakage in Mitochondrial Inheritance

While primarily maternal, some species capacitate paternal leakage, where a small number of paternal mitochondria are inherited. In mice, the ratio is approximately 1-4 paternal mitochondria per 100,000 maternal mitochondria per generation.

Human Mitochondrial Diseases

Mitochondrial diseases can arise due to two principal mechanisms:

  • Transmission strictly from mother to offspring, adhering to maternal inheritance templates.

  • Mutations that occur in somatic cells due to aging, wherein mitochondria are particularly vulnerable to DNA damage from free radicals and have limited repair capabilities.

Common Human Mitochondrial Disorders

Some notable mitochondrially inherited disorders include:

  • Leber hereditary optic neuropathy (LHON): Associated with mutations in several mitochondrial genes affecting electron transport chain proteins.

  • Neurogenic muscle weakness: Linked to ATPase6 mutation impacting ATP synthesis.

  • Mitochondrial myopathy: Affected by mutations in tRNA for leucine.

  • Maternal myopathy and cardiomyopathy, which also stem from mutations in tRNA for leucine.
    Symptoms of these diseases often rely on the ratio of mutant to normal mitochondrial DNA (heteroplasmy), determining the severity of such diseases and phenotypic outcomes of affected cells.

Epigenetic Inheritance

Epigenetic inheritance entails modifications to gene expression that don’t alter the underlying DNA sequence permanently across generations. Though such changes impact individuals' lives, they are not confined to Mendelian inheritance patterns. For example, processes like X-chromosome inactivation and genomic imprinting illustrate this form of inheritance, which constitutes a violation of the Law of Unaltered Gene Transmission besides rare mutations.

Genomic Imprinting

Genomic imprinting refers to heritable modifications to nuclear genes that alter expression, where the expression of a gene diverges based on whether it is inherited maternally or paternally. This results in a non-Mendelian pattern where offspring express either the maternal or paternal allele and not both, a phenomenon termed monoallelic expression.

Example of Genomic Imprinting in Mice

An illustrative case for genomic imprinting is the Igf-2 gene in mice:

  • This gene encodes the growth factor insulin-like growth factor 2.

  • Imprinting results in the expression of the paternal Igf-2 allele while silencing the maternal one.

  • If the paternal allele is mutated, it leads to dwarfism in offspring only if passed on from the father, mimicking patterns of imprinting.

Understanding Imprinting Effects

In the example of Igf-2, two parental genotypes yield:

  • A homozygous mother, Igf2-Igf2 (silent allele) crossed with a paternal Igf2 lgf2 (expressing allele) would produce normal offspring where only the lgf2 allele is expressed in somatic cells.

  • Conversely, in offspring of a homozygous paternal Igf2-Igf2 and a lgf2 mother, the Igf2 allele leads to dwarf offspring due to selective expression.

Stages of Imprinting

Genomic imprinting processes can be segmented into three crucial stages:

  1. Establishment of the imprint during gametogenesis, services by the parental contributions.

  2. Maintenance of the imprint throughout embryogenesis and in adult somatic cells, ensuring stable gene expression.

  3. Erasure and reestablishment of the imprint in the germ cells of offspring, which adjusts the imprint according to the parent it is derived from.

Biological Significance of Imprinting

Approximately 100 genes are recognized as imprinted in humans, and several genetic diseases are directly tied to these imprinted genes. Examples of imprinted genes and their functionalities in humans include:

  • WT1 (Maternal): Tumor-suppressor gene critical for Wilms' tumor suppression.

  • INS (Paternal): Encoding insulin for cell growth and metabolism.

  • Igf2 (Paternal): Plays a critical role in growth, resembling insulin's biological functions.

  • Igf2R (Maternal): Functions as a receptor for insulin-like growth factor 2.

While only around 1-2% of human genes display imprinting, the ones studied have provided insights into developmental biology and pathology.

Maternal Effect Inheritance Concept

Maternal effect inheritance reveals that only the mother's genotype dictates the phenotype of her offspring, with the father's and offspring's genotypes being irrelevant. This effect stems from maternally cast gene products that accumulate and influence the early developmental trajectory of the offspring.

Example of Maternal Effect: Snail Coiling in Lymnaea

The first documented example of maternal effect genes was in the coiling of the snail Lymnaea, introduced by Arthur Boycott in the 1920s. In this species, shell coiling direction leads to two observable phenotypes:

  • Right-handed (dextral)

  • Left-handed (sinistral)
    Reciprocal crosses and further analyses exhibited a non-Mendelian inheritance pattern dictated solely by maternal genotype.

Mechanism of Coiling Control

The maternal effect gene governs coiling direction, posited by Alfred Sturtevant as:

  • A single gene with two alleles (D and d).

  • Dd mothers invariably produce dextral offspring regardless of the offspring's own genotype due to maternal contributions.

  • Conversely, dd mothers yield sinistral offspring, whites influencing phenotype regardless of the infant's genetic constitution.

Oogenesis and Maternal Effect Inheritance

Oogenesis plays a critical role in maternal effect inheritance:

  • Oocytes acquire nutrients from surrounding diploid nurse cells, while the oocyte itself becomes haploid.

  • Maternal genetics shape the oocyte's content, influencing embryonic development post-fertilization, leading to differential phenotypes in offspring based on maternal genotypes despite genetic variability among offspring.

Conclusion on Maternal Effect Implications

Maternal effect genes prove pivotal in early embryogenesis, guiding crucial processes such as cell division, cleavage patterns, and establishing body axes. Geneticists have identified numerous maternal effect genes in model organisms like Drosophila, demonstrating profound effects during the initial stages of development. Mutations within these genes have significant implications, often resulting in dramatic, early developmental phenotypes, thus underscoring their importance in genetics.