Non-Traditional Inheritance

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1. Explain the etiology of somatic and germline mosaicism

Back 1

First, you may want to review (1) the types and (2) the causes of genetic mutations, from the lecture "Human Genetic Variation". With those possibilities in mind, somatic vs. germline mosaicism is just a matter of which cells underwent genetic mutations during embryonic development.

If a somatic cell (non-sex cell) suffers a genetic mutation during development, then all the cells (or tissues and organs) that arise from that somatic cell will have that mutation. Other cells arising independently won't have that mutation. So now you have two genotypes in a single organism: mosaicism.

If in development mutations occur in cells that eventually give rise to gametes (sperm/eggs), then you have germline mosaicism. Unlike mutations in somatic cells, germline mutations can be passed on to the next generation.

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2. Explain how mosaicism can account for an unusual inheritance pattern (e.g. more than one child affected with an autosomal dominant disorder without any family history).

Back 2

This objective refers to germline mosaicism, not somatic mosaicism - this is because mutations in somatic cells cannot be inherited. The red flag for germline mosaicism in a pedigree / clinical scenario is when neither parent has the autosomal dominant (AD) disorder and yet 'more than one child' has the disorder.

While it is completely possible that each affected child independently suffered the AD
disorder mutations during development, this is much less likely than if one parent has germline mosaicism and passed on the same mutation to the affected children.

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3. Describe the typical features of mitochondrial inheritance

Back 3

The egg supplies the zygote with all of its mitochondria, therefore, they are always maternally inherited. Disorders due to mutation in mtDNA therefore display maternal inheritance. Another important feature is that when cells divide, the mitochondria are not evenly distributed in
the cytoplasm of the daughter cells, but instead are randomly distributed. Each cell therefore comtains a mixed population of mitochondria, so a single cell may have some mtDNA
that carry a mutation and some that do not. This heterogeneity in mtDNA composition is
called heteroplasmy.

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4. Describe how maternal inheritance and heteroplasmy result in the unusual features of mitochondrial inheritance

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1. Maternal inheritance: all of an individual's mitochondria originate from his/her mother's oocyte (female germ cell). This means only females, not males, can pass on the mitochondrial genotype/phenotype. Males can suffer from a mitochondrial disease, but they won't pass it on.

2. Heteroplasmy: this just means that mtDNA (mitochondrial DNA) can be different from mitochondria to mitochondria and from cell to cell. Mitochondria with different genotypes can certainly exist within a single cell. Also, unlike sexual reproduction, there aren't really rules to how mitochondria are divvied up to daughter cells.

3. **Threshold Effect: if a cell has plenty of mitochondria with normal mtDNA, and just a few with mutated mtDNA, then there may be no pathology arising from the mutated mtDNA. This implies a threshold level at which mutant mtDNA begins to manifest a problem. A note: different cells may have different threshold levels. For example, there is a lower threshold for energy-needy cells such as neurons and muscle. *It should be straightforward to see how this 'feature' implies incomplete/reduced *penetrance (not all progeny of the mother will show disease phenotype), variable expression (severity will depend on proportion of mutated mtDNA), and pleiotropy (different tissues, different effects).

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5. Define uniparental disomy and explain one mechanism by which occurs

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..can't define it better than in syllabus:
"Uniparental disomy (UPD), occurs when a child inherits both copies of a chromosome pair (or region of a chromosome) from the same parent."

The most common mechanism is, in short, meiotic nondisjunction followed by trisomic rescue.

Explanation: in meiosis, nondisjunction (in either meiosis I or II) produces a gamete with
two copies of a chromosome instead of the usual one. If this gamete later successfully becomes part of the zygote, then the zygote will be trisomic for that chromosome. Now it turns out that zygotes can protect against trisomy by eliminating one of the 3 copies of the chromosome - if this trisomic rescue eliminates the chromosome copy from the normal gamete, then you're left with two chromosomal copies from the same parent.Swounds.

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6. Define genomic imprinting and describe its effect on gene expression

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Genomic imprinting is an epigenetic phenomenon in which an allele is transcriptionally active or inactive based on maternal or paternal origin.

An imprinted gene is not expressed (i.e. transcriptionally inactive).

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7. Explain how imprinting can be involved in human genetic diseases

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?

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8. Explain the etiology of Prader-Willi syndrome and Angelman syndrome, and describe 3 mechanisms that can result in these disorders

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The two 'classic' examples given in the syllabus are Prader-Willi syndrome (PWS)
and Angelman syndrome (AS). In either disorder, expression of genes contained in an
entire chromosomal region (15q11-q13) is completely lacking because, in that region, (a) one chromosome (of the inherited pair) is imprinted, while (b) the other, non-imprinted chromosome

has suffered a deletion. Important genes aren't expressed, and you're left with a disorder. This is mechanism #1.. put simply, imprinting + deletion in homologous chromosome.
(Note: the chromosomal region in PWS is maternally imprinted, while the chromosomal region in AS is paternally imprinted.)

mechanism #2:
Imprinting + uniparental disomy can also lead to the same disorders. How? Take PWS, for which the chromosomal region is maternally imprinted. If a mother passes on two copies of the chromosome in question, and the father's copy is eliminated in trisomic rescue, then the result is progeny who has both chromosomal copies imprinted. So here you get PWS without even having necessarily inherited the deletion.

mechanism #3:
Imprinting defect: if the cellular machinery that performs imprinting isn't working properly, then diseases associated with imprinting apparently can be affected. This isn't explained in the syllabus with any specifics. However, one guess about what might happen, especially with respect to PWS and AS, is that the imprinting machinery (for whatever reason) erroneously imprints both paternal and maternal copies of the chromosomal region. As with mechanism #1 and #2, this would effectively inactivate gene expression for that region, leading to the disorder.

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9. Explain the concept of anticipation and describe the role of unstable repeats in this phenomenon

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Anticipation is when a disease phenotype becomes progressively worse in successive generations. Worse = earlier onset and greater severity.

The molecular mechanism of anticipation originates in tri-nucleotide repeat sequences, contained in some (potential) disease gene. These repeat sequences are unstable, specifically in that they
can become longer and longer in each new generation. (This sequence expansion actually occurs during meiosis.) For the gene involved, this presumably leads to mutant versions that are more and more problematic in terms of disease. This shouldn't be too surprising - the longer you make the mutant addition to the original wild-type protein, the more problems you will incur.

The diseases that follow this mechanism are unstable repeat expansion diseases, many of which are neurological.