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BIOL312 Medical Genetics > Lecture 7: Epigenetics and disease > Flashcards

Lecture 7: Epigenetics and disease Flashcards

1
Q

What are three common characteristics of Angelman Syndrome?

A
  1. Developmental delay
  2. Speech impediment
  3. jerky movements, hand flapping
  4. happy disposition
  5. microcephaly
  6. seizures
    7 abnormal EEG (abnormal brain activity)
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2
Q

What are three common characteristics of Prader-Willi Syndrome?

A
  1. hypotonia (low muscle tone)
  2. poor feeding in infancy
  3. insatiable appetite later in life
  4. obesity
  5. short stature
  6. compulsive behaviour
  7. strabismus
  8. hypogonadism/poor sexual development
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3
Q

What is the deletion commonly responsible for both Angelman and Prader-Willi syndrome?

A

deletion of up to 6 Mbp on chromosome 15q11.2 - q13.1

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4
Q

(for Angelman and Prader-Willi Syndrome) Why can a deletion occur within chromosome 15 and what are the two types of deletions that can occur?

A

Repeat sequences in break points can undergo aberrant meiotic recombination resulting in type I or type II deletions:
Type I = deletion between break point 1 and break point 3.
Type II = deletion between break point 2 and break point 3.

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5
Q

What explains the difference in PWS and AS despite being caused by the same chromosomal deletion?

A

Genomic imprinting

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6
Q

What is genomic imprinting?

A

An epigenetic trait in which the expression of genes from one chromosome is silenced but there is no change to the DNA sequence

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7
Q

What does genomic imprinting mean for the 15q11.2-13.1 region?

A

Some genes in this region are expressed only on the paternal chromosome (silenced on the maternal chromosome) and some genes are only expressed on the maternal chromosome (silenced on the paternal chromosome)
- this means in a usual situation, an individual will still express all genes as they have inherited one of each chromosome from their mother and father

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8
Q

How does genomic imprinting relate to an individual having Prader-Willi syndrome?

A
  • Type I deletion in paternal chromosome means that the individual won’t express any of the paternal genes in this region since they have been deleted on the paternal chromosome and imprinted on the maternal chromosome
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9
Q

How does genomic imprinting relate to an individual having Angelman Syndrome?

A
  • Type I deletion in maternal chromosome means that the individual won’t express any of the maternal genes in this region since they have been deleted on the maternal chromosome and imprinted on the paternal chromosome
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10
Q

What is genomic imprinting an example of?

A

An epigenetic trait

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11
Q

What is the definition of an epigenetic trait?

A

a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence

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12
Q

What are the three mechanisms involved in epigenetic modification of gene expression?

A
  1. methylation of cytosine residues in DNA causing it to be sequestered into heterochromatin
  2. Histone modifications
  3. Regulation of lncRNA (important in X-chromosome inactivation)
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13
Q

What epigenetic modification is responsible for genomic imprinting?

A

methylation of cytosine bases at CpG sites in differentially methylated regions (DMRs)

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14
Q

What are the two mammalian methyltransferases responsible for genomic imprinting?

A
  1. de novo methyltransferases = fully unmethylated DNA is methylated at the 5’ cytosine of CpG site on one strand (hemimethylated)
  2. maintenance methyltransferases = recognises heavily methylated DNA and adds methyl group to the CpG site of the opposite strand.
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15
Q

What happens when epigenetic methylation occurs in embryo and somatic cells?

A

the resulting gametes will have the same methylation pattern
(E.g. all oocytes/sperm will have the same methylation pattern as the maternal/paternal chromosomes)
These genomic imprints persist in the zygote somatic cells

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16
Q

True or false: If a chromosome of paternal origin is packaged into an oocyte, it will still have a methylation pattern that matches the paternal chromosome?

A

False: no, the methylation pattern will be imprinted to match that of the maternal chromosome since it is of maternal origin when passed on next.

(if this doesn’t make sense, covered on slide 12 of lecture 7)

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17
Q

Where does genomic imprinting occur?

A

Paternal (established in prospermatogonia in testes of foetus)
Maternal (established during oocyte maturation in meiosis)

18
Q

Why is genomic imprinting removed in primordial germ cells?

A

maternal and paternal imprints are removed in primordial germ cells so that the correct imprinting can be re-established in the gametes based on the biological sex of the individual (E.g. if the individual is female, the maternal and paternal imprints will be removed in the germ cells and the gametes will have have maternal imprinting, since all these chromosomes will have come from the maternal side)

(if this doesn’t make sense, covered on slide 12/13 of lecture 7)

19
Q

How are the PWS genes imprinted on the maternal chromosome 15?

A
  1. imprinting centre (IC) of maternal chromosome is methylated sequestering adjacent region into heterochromatin
  2. blocks the transcription of PWS genes flanking the IC site silencing them
  3. Angelman syndrome genes (ATP10A and UBE3A) still active
20
Q

How does PWS occur and what causes PWS?

A

Occurs when there is a deletion of 15q11.2-13.1 in paternal chromosome and maternal chromosome is silenced.

Cause:
particular deletions implicate disruption to the cluster of small nucleolar RNAs (snoRNAs) located in introns of SNHG14 (small nuclear host gene 14) transcript

21
Q

How does the SNHG14 transcript differ in the brain?

A

highest expression levels and longest transcript in the brain

22
Q

How does the SNHG14 transcript differ in non-neuronal cells?

A

Transcript terminates after the SNORD116 locus

23
Q

How are the AS genes imprinted on the paternal chromosome in non-neuronal cells?

A
  1. imprinting centre (IC) of the paternal chromosome is unmethylated and gene expression is activated
  2. SNHG14 transcript terminates after SNORD116 locus
  3. most PWS genes are expressed as well as AS genes including UBE3A
24
Q

Which snoRNA cluster is most important in PWS? and how do they know this?

A

SNORD116 cluster of snoRNAs

They know this because there are some patients with PWS that have rare small deletions that disrupt SNORD116 and still have the disease (so this must be an important gene in disease implication)

25
Q

How are the AS genes imprinted on the paternal chromosome in neuronal cells?

A
  1. The imprinting centre (IC) is unmethylated on paternal chromosome so gene expression activated
  2. The SNHG14 transcript is longest in neuronal cells and extends past SNORD116 to produce an antisense transcript of the UBE3A and ATP10A genes
  3. This recruits silencing complexes that silences these AS genes
26
Q

What type of effect is imprinting of AS genes in neuronal cells an example of?

A

Secondary imprinting effect

27
Q

What causes angelman syndrome?

A

loss of UBE3A function in the brain due to deletion at 15q11.2-13.1 (plus paternal imprinting) or UBE3A point mutation on maternal chromosome or paternal uniparental disomy)

28
Q

Why can UBE3A disruption result in angelman syndrome?

A

UBE3A is an E3 ubiquitin ligase, one of the targets Ephexin 5 is responsible for development of an excitatory synapse.
Thus, if UBE3A is absent, Ephexin 5 cannot be degraded and this inhibits the development of an excitatory synapse

29
Q

How can uniparental disomy cause PWS?

A

Uniparental maternal disomy of chromosome 15 means offspring possesses two maternal chromosome 15s (each with imprinted PWS genes) which is equivalent to deletion of the paternal chromosome

30
Q

How can uniparental disomy cause AS?

A

Uniparental paternal disomy of chromosome 15 means offspring possesses two paternal chromosome 15s (each with imprinted AS genes) which is equivalent to deletion of the maternal chromosome

31
Q

In PWS/AS cases with uniparental disomy, what would their FISH and aCGH results look like?

A

They would both be normal as all the genes are present since there is no deletion (but they just aren’t all expressed)

32
Q

What method can be used to confirm the diagnosis of PWS/AS in cases caused by uniparental disomy?

A

Methylation specific PCR to identify the methylation status of the imprinting centre to determine if maternal (IC methylated) or paternal (IC unmethylated) chromosome is present

33
Q

How does methylation specific PCR work to diagnose PWS/AS cases caused by uniparental disomy?

A
  1. treat DNA with sodium metabisulfite:
    - methylation protects cytosine from deamination by sodium metabisulfite so cytosines remain
    - unmethylated cytosines aren’t protected so are deaminated to uracil
  2. the treated DNA sequences are used as template for DNA amplification (primers specific for methylated and unmethylated DNA are used to give different sized products that are separated by electrophoresis
34
Q

Why is one X chromosome inactivated in females with two X chromosomes and when does this silencing occur?

A
  1. X chromosome inactivated for dosage compensation
  2. This silencing/inactivation occurs randomly at the blastocyst stage in each cell by sequestering it into heterochromatin into a Barr body
    - each blastocyst randomly generates a clone with the same X inactivation
35
Q

What is the result of X-inactivation at the blastocyst stage by each cell?

A

Each blastocyst cell clones and all subsequent cells will have the same X inactivation
- this means biological females have a mosaic of cells with either the maternal or paternal X-chromosome active

36
Q

Explain how the X-inactivation occurs at the blastocyst stage?

A
  1. initially both X chromosomes express the lncRNA Xist, which is unstable and degraded
  2. randomly one X chromosome will start expressing the anti-sense lncRNA Tsix, which negatively regulates the Xist transcript to promote degradation of Xist expressed by the same chromosome
  3. the other X chromosome will continue to express Xist, which coats the X chromosome from which it is transcribed –> this X-chromosome is squestered into heterochromosome, histones compact chromosome into a Barr body.
37
Q

The active X chromosome expresses all regular genes with the exception of ___?

A

Xist

38
Q

True or False: the inactive X chromosome doesn’t express Xist?

A

False: the inactive chromosome is the only one that stably expresses Xist (coats it encourages Barr body formation)

39
Q

What are the consequences of X-inactivation for carriers of X-linked diseases?

A

Due to random nature of X-inactivation in biological females, half of the cells will have the normal wild type chromosome and gene expression, where as half will have the mutation (these are called manifesting carriers)
- the effects of X-activation in manifesting carriers depends on the nature of the gene product and the number/location of cells containing the inactivated X chromosome

40
Q

Go over the rest of slide 27 ………………………………………………………………………………………………….

A
41
Q

Explain how Duchenne muscular dystrophy can vary based on X inactivation status and biological sex (males with DMD and female manifesting carriers).

A

DMD is X-linked recessive disorder
- Males with DMD = mutated X gene in every cell = no dystrophin protein in any muscle fibres
- Females (manifesting carrier - the unaffected X-chromosome is randomly inactivated) = mutated X in some cells = reduced nonuniform expression of dystrophin protein in muscle tissue = some effect

BIOL312 Medical Genetics (10 decks)

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