Lecture 21: Epigenetics, Genomic imprinting and dynamic mutation Flashcards
What is epigenetics
A stably heritable (via mitosis) phenotype between cells resulting from structural changes in the chromosome without alterations in DNA sequence
ie methylation
What does DNA methylation mean
A methyl group is added to the CpG regions in gene promoters that causes transcriptional silencing.
How is DNA methylation transferred between cells in mitosis and then how can it be reversed to treat cancers driven by methylation
Methyltransferase enzyme that add methyl groups to cytosine residue . It can be reversed if they are inhibited or removed in early development
How does X inactivation work -
non coding RNA called XIST is transcribed from X chromosome and binds to the same chromosome to interfere with any more transcription. This recruits proteins that are methylated to cover the chromosome.
What is Genomic imprinting and what is it caused by
Restriction of expression to either maternal or paternal allele in somatic diploid cell, not whole chromosome. It occurs because of specific proteins binding imprinting genes during gametogenesis and early embryogenesis to protect it from a global methylation
What is the relationship between methylation in the primordial germ cells to post implantation
The germ cells methylation is erased and then restablished from birth (m) or to puberty (f) before at fertilisation there is a large erasure again at DNA replication and then slowly building up of methylation, except the imprinted genes are protected in this large erasure after fertilisation
What is Prader-Willi syndrome features vs Angelman features
Neonatal hypotonia, rapid weight gain after 1 year, hypogonadism, small hands and feet, short stature and behavioural obesity.
Angel man is mental retardation, happy expression, hypopigmentation
What causes Prader-Willi syndrome and compare to Angelman syndrome
The paternal allele of a region of chromosome 15 for SNRPN & NDN genes + snoRNA genes is deleted or not present and the maternal allele cannot take over because it is silenced due to imprinting.
Angelman is caused by deletion or inactivation of maternal allele of chromosome 15 for UBE3a in the brain and paternal allele silencing due to imprinting
How do disorders arise from methylation/imprinting in somatic cells
- Excess growth due to stopping the methylation of father copy of producing growth factor 2 and some mutation in the regulator of this growth factor product in the maternal gene
- Wilms tumour growth
- methylation of genes that regulate overgrowth
What is dynamic mutation and how does it relate to anticipation
Progressive expansion of repeat sequences; manly triplets.
Over generations this expansion is getting larger and larger, causing diseases to present earlier and more severely in newer generations. This is called anticipation
What is the Huntington disease caused by and how does it present
Caused by mutant HTT allele in chromosome 4 which has more than 26 CAG repeats to be mutant but more than 35 to become clinically presenting as well. The repeats cause toxic peptides which kill neuronal cells of the basal ganglia. especially
It presents as progressive motor disability involving both voluntary and involuntary movement and cognitive decline/changes in personality.
What is the mode of inheritance of huntingtons disease
Autosomal dominant inheritance so child has 50% chance of having disease . Occurs more commonly with paternal transmission as there is instability of CAG repeat during spermatogenesis. In the case of an asymptomatic parent they may have a reduced penetrance allele
