Lecture 23: Introduction to epigenetics, genomic imprinting, and dynamic mutations

Question 1

What is epigenetics?

Answer 1

An epigenetic trait is a stably heritable (mitosis) phenotype resulting from changes in DNA without alterations to the DNA sequence

i. e
- DNA methylation
- non-coding RNAs (i.e microRNA and IncRNA)
- Histone methylation and other modifications
- RNA methylation

Question 2

Where does methylation occur? and what does it cause?

Answer 2

Cytosine residues in CpG islands. (located in gene promoters)

• Causes transcriptional silencing
• Contributes to X chromosome inactivation (lyonisation)

Question 3

How is DNA methylation transferred between cell divisions?

Answer 3

Methyltransferase enzyme activity (methylation can be reversed if these are inhibited or sequestered)

Question 4

What causes x-inactivation / lyonisation?

Answer 4

A combination of DNA methylation and non-coding RNA called XIST working together-random inactivation of either maternal or paternal chromosome/allele

• Can lead to mosaic phenotype
• No longer useful for making RNA

Question 5

What is genomic/genetic imprinting? what causes it?

Answer 5

Restriction of expression to either the maternal or allele in somatic diploid cells

• Due to allele specific epigen mod. i.e cytosine methylation as a result of gamete specific proteins binding and imprinted genes during gametogenesis and early embryogenesis.
• Different tissues have different imprinted genes

Question 6

What does genomic imprinting cause?

Answer 6

• Causes different expression from genetically identical alleles based on parent of origin

Question 7

What are the two syndrome we study caused by genetic imprinting?

Answer 7

• Prader-willi syndrome

- Angelman syndrome

Question 8

What is prader willi syndrome clinical features?

Answer 8

• Failure to thrive in infancy and childhood
• Rapid weight gain after one year
• Dificits in brain
• Hypogonadism

Question 9

What causes prader willi syndrome?

Answer 9

• Paternal allele of a region of chromosome 15 is deleted or not present due to uniparental disomy
• Maternal allele cannot take over since its silenced due to genetic imprinting

In particular; Absence of the SNRPN and NDN genes along with clusters of snoRNA genes.

Overlaps with angelman syndrome because of same genes.

Question 10

What is the clinical presentation of angelman syndrome?

Answer 10

• Tongue thrusting
• Happy open mouth
• Motor retardation
• Happy children, frequent laugh
• Ataxia
• Hypotonia

Question 11

What causes angleman syndrome?

Answer 11

• Maternal allele of a region of chromosome 15 is deleted or inactivated
• paternal allele cannot take over since its silenced due to imprinting

Absence of UBE3A gene expression.

the affected genes are different between the two syndromes, they have different normal functions in different tissues

Question 12

What is methylation also associated with? and how?

Answer 12

Cancer
- Usually a growth enhancer being over expressed i.e IGF2 (lack of methylation) and then a deficiency of growth suppressor (excess methylation) in another gene on one allele. = Imbalance syndrome i.e Wilms tumour and familial paraganglioma

Question 13

What drives gene expression in cancer?

Answer 13

Somatic methylation drives gene expression in cancer

Question 14

What does methylation of somatic cells in cancer allow for?

Answer 14

Therapeutic inhibition of DNA methyltransferase

Question 15

What is dynamic mutation?

Answer 15

Progressive expansion of triplet repeats through generations i.e huntington disease.

Symptoms in later generations often occur at younger ages and are more severe

Question 16

What are some more examples of conditions with dynamic mutation?

Answer 16

Huntingtons disease
Myotonic dystrophy
Cerebellar ataxia
Fragile X disease

Question 17

Whats required for the clinical diagnosis of huntingtons?

Answer 17

• Progressive motor disability both voluntary and involuntary
• Cognitive decline / changes in personality
• Family history consistent with autosomal dominant inheritance.

Anticipation and progression….

Question 18

What are normal allele triplet repeat sizes for HTT? whats not normal

Answer 18

Normal <26 CAG repeats
Intermediate 27-35 CAG repeats, no symptoms, but children at risk of inheriting mutant allele if parent is male.
Mutant >36CAG repeats, full penetrance 40+

Question 19

How does the CAG expansion cause disease?

Answer 19

Increased triplets results in incorrect HTT protein folding., effect on neuronal cells through gain of function ; creation of toxic peptides

Question 20

What is meant by anticipation when it comes to HD?

Answer 20

Increasing disease severity or decreasing age of onset observed in successive generations.
- Occurs more with paternal transmission (instability of CAG repeat during spermatogenesis)

Question 21

What is the risk for family members in HD?

Answer 21

• Usually have an affected parent, (de novo is rare)
• Asymp parent or reduced penetrance
• Offspring have 50% chance (heterozygous) homozygous is very rare….

Question 22

What can be done for molecular genetic testing of HD?

Answer 22

Diagnostic testing (Confirmatory)
Predictive testing (presymptomatic)
Prenatal`

Question 23

What is the function of diagnostic testing in HD?

Answer 23

• Confirms disorder

- Undertaken after assessment by neurologist

Question 24

What is the function of predictive testing in HD?

Answer 24

• Confirms mutation that confers high risk of disorder prior to onset of disease
• Only undertaken after neurological assessment and counselling

Question 25

What is the function of prenatal testing?

Answer 25

• Issues regarding disclosure of status of parent

- Exclusion testing (excludes parent, looking for grandparent allele)