Epigenetic Flashcards
What is an epigenetic trait
An epigenetic trait is a stably heritable phenotype resulting from
changes in DNA without alterations to the DNA sequence
Examples of epigenetics
o DNA methylation
o non-coding RNAs (e.g. microRNA, lncRNA)
o Histone methylation and other modifications
o RNA methylation
Where does Methylation of DNA in mammalian cells occur
- CpG methylation of gene promoters causes…
-CpG methylation is transmitted through?
cytosine residues in CpG
islands
CpG methylation of gene promoters causes transcriptional silencing
CpG methylation is transmitted through cell divisions by methyltransferase
enzyme activity
Methylation can be reversed if methyltransferases are inhibited or sequestered (as occurs in early
development)
What is X inactivation
A combination of DNA methylation and a non-coding RNA called XIST working
together - random inactivation of either maternal or paternal chromosome/allele.
What is genomic imprinting
- Restriction of expression to either the maternal or paternal allele in somatic
diploid cells - Causes different expression from genetically identical alleles based on parent of
origin
What are the Two different syndromes caused by
abnormalities in the maternal or paternal alleles at close imprinted loci
Prader willi syndrome and angelman syndrome
What is pradar willi syndrome symptoms
- mutation type
- Failure to thrive in infancy and early childhood
- Neonatal hypotonia
- Rapid weight gain after 1 year
- Behavioural obesity and short stature
- Almond-shaped eyes
- Hypogonadism
- Small hands and feet
- Skin hypopigmentation
- Behavioural problems
The paternal allele of a region of chromosome 15 (15q11-q13) is deleted
or not present due to uniparental disomy
* The maternal allele cannot take over since it silenced due to imprinting. In particular, causing absence of the SNRPN and NDN genes along with
clusters of snoRNA genes
Symptoms of angelman syndrome
- Typically a happy, open-mouthed expression
- Tongue thrusting
- Mental retardation
- Motor retardation, jerky movements
- Ataxia
- Hypotonia
- Seizures
- Sleep disturbances
- Happy children, laugh frequently
- Skin hypopigmentation
Causes of angelman syndrome
- The maternal allele of a region of chromosome 15 (15q11-q13) is deleted
or inactivated - The paternal allele cannot take over since it silenced due to imprinting
- In particular causing absence of UBE3A gene expression
PW vs angelman chromosome affected
Pradar= paternal copy deleted
Angelman
= maternal copy deleted
Importance of Methylation in Cancer
Therapeutic Target
* Abberant Methylation is a hallmark of cancer - switching off global
methylation (e.g. 5-azacytidine) via blocking methyltransferases can
reactivate gene expression
Biomarker Target
* Methylation signatures are cell type and disease state specific
* Testing of DNA in tissues or biofluids can indicate diagnosis, prognosis
What is a Dynamic Mutation
-common diseases caused
- Progressive expansion of repeat sequences; mainly triplet repeats
Huntington disease
Myotonic dystrophy
Cerebellar ataxias
Fragile X disease A
Clinical Diagnosis of HD
-gp level
- Progressive motor disability involving both voluntary and involuntary
movement - Mental disturbances including cognitive decline and/or changes in
personality - Family history consistent with autosomal dominant inheritance
Allele sizes of huntingtons
Normal: ≤ 26 CAG repeats
- no clinical effects, stable in transmission
Intermediate: 27 - 35 CAG repeats
- no symptoms of HD, but possibility of child inheriting “mutant allele” if affected parent is
male
Mutant: ≥ 36 CAG repeats
- reduced penetrance alleles: 36 - 39 repeats
- full penetrance alleles: ≥ 40 repeats
HD risks to family members
Parents of proband
* most individuals with HD have an affected parent (de novo mutations causing HD
are rare)
* either asymptomatic parent of an affected individual may have a reduced
penetrance allele (CAG repeat 36-39)
Sibs of proband
* risk depends on genetic status of parent
Offspring of proband
* each child of individual with HD has a 50% chance of inheriting the mutation as a
result of heterozygosity for the HD mutant allele (homozygosity is very rare)
Molecular Genetic testing of HD
Diagnostic (confirmatory)
* confirms disorder
* undertaken after assessment by neurologist
Predictive (presymptomatic)
* confirms mutation that confers high risk of disorder prior to onset of disease
* only undertaken after neurological assessment and counselling
Prenatal
* issues regarding disclosure of status of parent
* exclusion testing (avoids definitively testing a parent by looking for the inheritance of
affected grandparental allele to give a ’50% risk’)
