38 Questions
What is the outcome of genomic imprinting?
Expression of genes from only one parental chromosome homologue
How do imprinted genes differ from non-imprinted genes?
They are often involved in placental and embryonic development
What is the function of an imprinting control region (ICR)?
To regulate the expression of multiple imprinted genes in a cluster
What is the cause of imprinting disorders?
All of the above
What is the outcome of UPD?
Inheritance of both copies of a chromosome from the same parent
Why do familial cases of imprinting disorders arise from mutation rather than from chromosomal nondisjunction and UPD?
DNA methylation is reset between generations
What is the relationship between environmental factors and the genome?
Environmental factors can cause epigenetic changes
What is a challenge in determining whether an observed epigenetic change is causal or secondary to the phenotype?
Both a and b
What is the outcome of the two waves of epigenetic reprogramming?
Erasure and re-establishment of epigenetic marks
Why is it important to understand mechanisms conferring non-genetic effects?
To understand the mechanisms underlying disease
What is the term for the critical level of mutant mtDNA in a cell that must be exceeded before a biochemical effect is detected?
Threshold Effect
Why is the level of heteroplasmy not fixed in an individual?
Because mitochondrial DNA replicates stochastically
What is the term for the random distribution of mitochondria to daughter cells during cytoplasmic division?
Stochastic segregation
Why do the levels of heteroplasmy vary widely between mother and child?
Because of the bottleneck effect
What is the term for the phenomenon where a person with a mtDNA mutation does not show the associated phenotype?
Reduced penetrance
What is the environmental factor that triggers the hearing loss phenotype in individuals with the mtDNA mutation?
Aminoglycoside antibiotics
Which tissues are primarily affected by mitochondrial disorders?
Muscle and brain
What is the name of the technique allowed by the UK government in 2015 to prevent the transmission of mitochondrial disease?
Mitochondrial therapy
Why are mitochondrial diseases genetically and phenotypically diverse?
Because of the interaction with the nuclear genome and environment
What is the purpose of the bottleneck effect in germline development?
To randomly sample the mitochondrial population
When do epigenetic marks in male germline cells typically get established?
During foetal development
What mechanism is not involved in the erasure of epigenetic marks after fertilisation?
Genetic inheritance
Which type of cell marks the beginning of epigenetic reprogramming in primordial germ cells?
Prospermatogonia
Which cells are marked by new epigenetic patterns in females after birth?
Growing oocytes
What is the ultimate goal of resetting DNA to a stem cell state post-fertilization?
To produce all cell types needed for the embryo and extraembryonic tissue
What are genomic imprints resistant to?
Second wave of epigenetic reprogramming
Which process is involved in the progressive re-establishment of epigenetic marks around the time of implantation?
Gene regulation for early embryonic lineages
What best describes the inheritance of epigenetic information?
Not inherited through generations
What is a known effect of undernourishment of the embryo in utero in mice?
Developmental delay
In what generation would effects need to be observed for an environmentally-induced trait to be considered a true inherited transgenerational effect?
F3
Which historical event provides data on how in utero nutritional compromise can lead to adult onset disease in humans?
The Dutch Hunger Winter
How many genes does the mitochondrial genome contain?
37
Which hypothesis suggests how the mitochondrial genome arose?
Endosymbiont Theory
How is mitochondrial DNA inherited?
Maternally
What happens to sperm mitochondria upon fertilization?
They are degraded
What is the term for cells containing a mixed population of normal and mutant mtDNAs?
Heteroplasmy
What type of transcript is generated from a single promoter in mitochondrial genomes?
Multigenic
What characterizes the mitochondrial genome compared to the nuclear genome?
All but 1kb of it makes a functional gene product
Study Notes
Epigenetic Reprogramming
- Epigenetic information is not inherited from one generation to the next, unlike genetic information.
- During germ cell development, epigenetic marks are erased early in primordial germ cell (PGC) development, allowing new marks to be established.
- In the male germline, epigenetic marks are established during fetal development, while in the female germline, marks are established after birth, during the growing oocyte phase.
- There are two phases of genome-wide epigenetic erasure and re-establishment: the first occurs during germ cell development, and the second occurs immediately after fertilization.
Genomic Imprinting
- Genomic imprints are DNA methylation marks that are established in different places in the male and female germlines and are resistant to epigenetic reprogramming.
- These imprints allow for the retention of a memory of parental origin on chromosomal regions containing imprinted genes.
- Imprinted genes are often involved in placental and embryonic development, as well as postnatal metabolism and behavior.
- The monoallelic expression of an imprinted gene is regulated by DNA methylation that differs on the two parental chromosomes.
Imprinting Disorders
- Imprinting disorders arise from the mis-expression of imprinted genes and can be caused by mutation, uniparental disomy, or epimutation.
- Epimutation causes the imprinting control region (ICR) to lose its appropriate differential methylation status, leading to abnormal imprinting.
- Most cases of imprinting disorders are sporadic, but occasionally they can be passed on in families and show parental origin effects in their pattern of inheritance.
Transgenerational Epigenetic Inheritance
- There is evidence that the environment can influence phenotype in ways that do not appear to arise from genetic mutation.
- However, it is challenging to determine whether an observed epigenetic change associated with an environmental influence is causal or a secondary consequence of the phenotype.
- Studies have shown that the environment a conceptus is exposed to in utero can have an influence on adult onset diseases after birth.
- However, it remains unclear whether an environmentally-induced trait can be inherited across generations.
Mitochondrial Inheritance and Disease
- The mitochondrial genome is 16.5kb, circular, and contains 37 genes with no introns.
- Mitochondrial genetics displays unusual features, including matrilineal inheritance and the ability to have a mixed population of normal and mutant mtDNAs (heteroplasmy).
- Mitochondrial disorders can show reduced/incomplete penetrance of the phenotype in individuals with the same mutation due to factors such as variable levels of heteroplasmy and interactions with the nuclear genome and environment.
- Mitochondrial replacement therapy (MRT) has been approved in the UK and involves the transfer of nuclear genetic material into a donor egg containing healthy mitochondria to generate a healthy baby free of mitochondrial disease.
Learn about the process of epigenetic reprogramming, where epigenetic marks are erased and re-established during germ cell development.
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