NON-MENDELIAN INHERITANCE

OBJECTIVES

• Understand how maternal effect influences the phenotype of the offspring and the molecular basis of this pattern of inheritance

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• Understand the process of epigenic inheritance, dosage compensation, genomic imprinting, and X inactivation in mammals

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• Know the origins of extranuclear genomes.
• Understand the patterns of inheritance associated with extranuclear inheritance

OUTLINE

• Maternal Effect
• Epigenic Inheritance
• Extranuclear Inheritance

Non-Mendelian Inheritances?

• Inheritance that is not obey the principle of Mendelian rules

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• Observed in many genes

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MATERNAL INHERITANCE

• Maternal effect refers to the inheritance pattern of nuclear genes in which the genotype of the mother directly determines the phenotype of the offspring, regardless of the genotype of the father or offspring.

Maternal Effect Genes

• Maternal effect was first described by A.E. Boycott (1920s) in his studies of the water snail, Limnea peregra

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• Shells of this species are arranged in a right-handed (dextral) or left-handed (sinistral) configuration
• Reciprocal crosses of sinistral and dextral individuals produced offspring that did not follow Mendelian patterns of inheritance.

• Sturtevant explained the maternal effect pattern of dextral (D) and sinistral (d) coiling (figure 7.1).
• The genotype of the mother determines the phenotype of the offspring.
• The genotype of the father has no influence of the offspring.
• An offspring’s genotype has no influence on its phenotype. But the genotype of a female offspring will determine the phenotype of its offspring.

Figure 7.1

Maternal Effects and Embryonic Development

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• The molecular and cellular basis of maternal effect can be explained by examining the process of oogenesis in females (Figure 7.2a).

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a. Surrounding the oocytes are the nurse cells (2n). In the nurse cells both copies of the gene encoding coil orientation are active. The nurse cells transport their gene products (mRNA and proteins) into the oocyte (Figure 7.2)

b. If the Dd or DD are released into the oocyte, it will have dextral coiling.

c. If dd is released into the oocyte, it will have sinistral coiling.

• Maternal effect genes encode for RNA and proteins that play an important role in the early stages of embryogenesis.
• Studies of Drosophila melanogaster have indicated that dozens of maternal effect genes influence early embryonic development.

EPIGENETIC INHERITANCE

• Epigenetic inheritance represents a modification to a nuclear gene or chromosome that alters gene expression. However, this gene expression is not permanently changed over several generations
• The changes usually persist for the individual’s lifetime and affect the phenotype of the individual
• Epigenetic modifications do not change the DNA sequence

• Two examples of epigenetic inheritance are dosage compensation and genomic imprinting
• Dosage compensation offsets the differences in the number of sex chromosomes in the sex of a species.
• Genomic imprinting occurs prior to fertilization and effects a single gene or chromosome.

Dosage Compensation and Equality in the Sexes

• Dosage compensation regulates the expression of genes on the sex chromosomes so that the genes product is the same in both sexes

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• The process was first described by Muller (1932) in his studies of eye color mutations in Drosophila

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a. Females homozygous for apricot eyes had the same eye color as hemizygous males, indicating that the expression of the gene was being regulated.

• In mammals, the expression of the X-linked alleles are regulated by a mechanism called X inactivation
• In C. elegans (a nematode), XX individuals are a hermaphrodites, while X individuals are males. The XX individual compensates for this by reducing gene expression by 50%

• In Drosophila, the expression of many X-linked genes is doubled to compensate.
• In other species, specifically those using the ZW sex determination system, such as the birds, the mechanism of dosage compensation is not clearly understood.

Dosage Compensation in Mammalian Females

• Barr and Bertram (1949) discovered a highly condensed structure in the somatic cells of female cats that was not present in male cats. This structure was called a Barr body
• The concept of X chromosome inactivation in mammals was first proposed independently by Lyon and Russell (1961).

• Ohno (1961) proposed that the Barr body was actually an inactivated chromosome
• Examination of calico cats and variegated mice was used by Lyon to propose a mechanism of X inactivation called the Lyon hypothesis (Figure 7.4)

a. Inactivated chromosomes are highly condensed, and most genes on the chromosome are not expressed.

X Inactivation in Adult Female Mammals

• According to Lyon hypothesis, somatic cells of female mammals will express the genes on one of the X chromosomes. This was experimentally tested by Davidson, Nitowsky, and Childs (1963).

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Their experimental system used the glucose-6 phosphate dehydrogenase (G-6-PD) enzyme. There are two alleles for

G-6-PD that can be distinguished by gel electrophoresis.

• Their experiment system (Figure 7.6) produced clones of epithelial cells from a heterozygous female, and then examined which alleles of the G-6-PD allele were being expressed. These results (pg. 172) supported the Lyon hypothesis.

Xic and Xist and X Inactivation

• The X-inactivation center (Xic) on the X chromosome is necessary to count the number of X chromosomes present in the cell.

a. Within the Xic region is a gene (Xist) that is required to compact the X chromosome into the Barr body (Figure 7.7)

b. The Xce region affects the choice of the X chromosome to be inactivated.

c. The TsiX region encodes a protein that is complementary to the Xist RNA. This is called antisense RNA. The TsiX RNA binds to, and inactivates, the Xist RNA. This action appears to be involved in X chromosome inactivation early in embryonic development.

• The process of X inactivation is divided into three phases.
• During initiation, one of the X chromosomes is targeted to remain active and the other is chosen to be inactivated.
• During the spreading phase, the Xist region promotes condensation. This starts near the Xic region and spreads in both directions along the chromosome.

c. The final phase is maintenance, during which the X chromosome is maintained as such during future cell divisions.

• Even though the inactivated chromosome is compacted, a few genes remain active, including pseudoautosomal genes that are also found on the X chromosome.

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Genomic Imprinting

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• Genomic imprinting is when a segment of DNA is marked, and this mark is retained and recognized throughout the life of the organism

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• The phenotypes caused by imprinted genes follow a non-Mendelian pattern of inheritance

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• Due to this marking, the offspring will express one of the two alleles. This is called monoallelic expression

• An example of genomic imprinting is the inheritance of insulin-like growth factor 2 (lgf-2) in mice (Figure 7.9)

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• Imprinting can be divided into three stages; establishment, maintenance, and erasure (Figure 7.10)

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• Imprinting may involve a single gene, a portion of a chromosome, or an entire chromosome.

Genomic Imprinting and DNA Methylation

• Genomic imprinting of some genes is known to involve differentially methylated regions (DMRs). The DMRs are methylated in the oocyte or sperm, but not both

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• Methylation usually results in an inhibition of gene expression, but not in all cases

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a. In two closely linked genes in humans (H19 and Igf-2), methylation inactivates H19 and activates Igf-2. the molecular basis of this is outlined in Figure 7.11a.

• Imprinted genes are differentially methylated during oogenesis compared to spermatogenesis (Figure 7.11b)
• In humans, the inheritance of disease such as Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with genomic imprinting. Both diseases are due to to a deletion on chromosome 15
• If the trait is inherited from the mother, the offspring has AS
• If the trait is inherited from the father, the offspring has PWS

EXTRANUCLEAR INHERITANCE

• In eukaryotic species, genetic material in the organelles is inherited by extranuclear inheritance, which is also called cytoplasmic inheritance.

Chromosomes of Mitochondria and Chloroplasts

• The fact that chloroplasts contain DNA was first suggested by Y. Chiba (1951)

• The DNA of mitochondria and chloroplasts is contained within a region of the organelle called the nucleoid
• There may be more than one nucleoid per organelle
• The genome of the organelle contains a single circular chromosome, which may be present in several copies (Table 7.3)
• The size of the genomes varies greatly among species.

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• mtDNA refers to mitochondrial DNA. In humans, the mtDNA is only 17,000 base pairs and contains relatively few genes
• cpDNA refers to chloroplast DNA, which tends to be larger than mitochondrial DNA (around 156,000 bp) and contains more genes

Extranuclear Inheritance

• Correns first described a non-Mendelian trait in the four-o’clock plant where the pigment of the offspring depended entirely on the maternal inheritance (Figure 7.16)

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• Maternal inheritance is due to the fact the mitochondria or chloroplasts are inherited only through the cytoplasm of the egg

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• Heteroplasmy is when a cell contains mitochondria or chloroplasts that differ in their traits (Figure 7.17)

Genetic Evidence of Extranuclear Inheritance

• Studies of inheritance patterns of mitochondria initially focused on yeasts and molds.
• Defective mitochondria grow more slowly, producing smaller colonies, called petites.
• Segregational petites have mutations in genes located in the nucleus that influence the nergy pathways.
• Vegetative petites have mutations in the mitochondria genome.

• Vegetative petites have several forms, two of which are neutral petites and suppressive petites
• The results of crosses involving these strains to wild-type strains are illustrated in Figure 7.18. These crosses provided strong evidence that the mitochondria have their own genetic material

• Neutral petites lack the majority of the mtDNA.
• Suppressive petites lack small segments of the mtDNA.
• Studies of chloroplast inheritance focused on the unicellular algae Chlamydomonas reinhardtii (Figure 7.19).

Variations in Mitochondria and Chloroplast Inheritance

• In heterogamous species, two kinds of gametes are made. Typically mitochondria and chloroplasts are inherited from the maternal parent, but this is not always the case.
• Sperm may provide mitochondria by paternal leakage, but this is a rare event.

Human Diseases Caused by Mitochondrial Mutations

• Several human diseases are the result of mitochondrial mutations
• These are usually degenerative disorders that follow a maternal inheritance pattern

Origins of Extranuclear Genomes

• The endosymbiosis theory explains how mitochondria and chloroplasts originated from bacterial cells (Figure 7.20).
• Genes in chloroplasts and mitochondria closely resemble bacterial genes but are not similar to eukaryotic nuclear genes.

• During evolution, some of the bacterial genes in these organelles have been lost or transferred to the nucleus.

a. This transfer is ongoing in plants but appears to have stopped in animals.

Symbiotic Infective Particles

• In some cases infective particles establish symbiotic relationships with the host and reside in the cytoplasm of the cell
• Examples are:
• paramecin protein in Paramecia aurelia
• CO2 sensitivity in Drosophila
• The sex ratio trait of Drosophila willistoni

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