Epigenetics & Imprinting Disorders Flashcards
Define epigenetics
- “over” or “above” genome
- “heritable changes in gene activity and expression (in the
progeny of cells or of individuals) and also stable, long-term
alterations in the transcriptional potential of a cell that are not
necessarily heritable” - “descendants can inherit traits
acquired by the habits of their parents and the interactions
between individuals and their environments is a key factor in the
evolution of species”
DNMTs
De Novo MethylTransferases, a family of enzymes
DNMTs function
- Catalyze the transfer of a methyl group from S-adenyl methionine (SAM) to the 5th carbon of cytosine to form 5-methylcytosine
- Dnmt3a and Dnmt3b establish new methylation patterns on
unmodified DNA - Dnmt1 functions during DNA replication to copy the DNA methylation pattern from the parental DNA strand onto the newly synthesized daughter strand
Location of methylation (3)
- Intergenic regions eg. transposable elements
- CpG islands – 70% of gene promoters here
- Witching genes at CpGs
Differentiate the Epigenetic tools: Writers, Readers, and Erasers
Writers: introduce modifications on DNA and histone tails
Readers: binds to modifications using specialized domains
Erasers: remove modifications introduced by the writers
Somatic vs Germline changes
Somatic mutations: not transmitted to progeny
Germline: can be transmitted to some or all progeny
Genomic Imprinting
- Premature germ cells: maternal and paternal imprints are erased
- Mature germ cells: parent-specific imprints that results in allele-specific expression in offspring
ie. active in maternal allele and silenced in paternal allele
Imprinting Disorders in Human Health
- Uni parental Disomy
- Deletion
- Epimutation
- Point Mutation
NOTE: methylation defect
Beckwith-Weismann Syndrome (BWS)
- macroscomia/ hemihyperplasia/ macroglossia
- neonatal hypoglycemia
- ear crease/ pits
- childhood cancers
Molecular genetics of BWS
Beckwith-Wiedmann Syndrome
Maternal:
- loss of methylation at imprinting control centre 2 (IC2) in 50% (epimutation)
- Gain of methylation at IC1 (maternal) in 5% (epimutation)
Paternal:
- Paternal Uniparental Disomy (UPD) in 20%
Silver-Russel Syndrome: features
• Asymmetric gestational growth restriction (relatively large head, small body)
• Post-natal growth failure
• Asymmetry, limb length discrepancy
• Prominent forehead/ Triangular face
• 5th finger clinodactyly (curved inward)
• Feeding difficulties
• Café-au-lait macules (birthmarks)
Molecular Genetics of SRS
Silver-Russell Syndrome:
Maternal:
- Uniparental Disomy (UPD) 7
- Somatic mosaicism for UPD11
Paternal:
- 11p15.5 ICR1 hypomethylation
Prader Willi Syndrome
- hypotonia (low muscle tone, floppy baby)
- hyperphagia = obesity
- Infertility
- Incomplete pubertal development
- Short stature
Molecular Genetics of PWS
Prader Willi Syndrome
Maternal:
- UPD chromosome 15
Paternal:
- Interstitial 5 to 6 Mb deletion of 15q11.2-q13
- Unbalanced chromosome rearrangement
Imprinting defect with deletion in the Imprinting Centre (IC)
- Epimutation without deletion in the IC
Angelman Syndrome : features
- Severe developmental delay, intellectual disability, speech impairment
- Gait ataxia (unstead wide based walk), tremulousness of the limbs
- Unique behaviour (frequent laughing, smiling, excitability)
- Seizures
- Microcephaly (small head size) with onset after birth
