Lect 5: Imprinting & Epigenetics Flashcards
Prader Willi (PW) and Angelman Syndrome (WS)
are microdeletion syndromes of the proximal arm of chromosome 15.
Cytogenetics is better at picking up
PW
FISH is better for picking up deletions in
both Angelman and PW
Inheritance patterns due to imprinting.
differences in the allele inherited from the father v the alleles inherited by the mother. (Imprinting affects the chromatin exposure which affects the gene expression but not its DNA sequence.
Before fertilization your sex chromosomes are imprinted as coming from you, your gender. You will have half of the complement paternally and hv half maternally. If I have a male child, he will inherit my genetic imprint and will have to convert it to his own gender’s imprint.
Vice versa for a male father passing on his imprint to his daughter.
Prader -Willli
there is a chromosomal deletion of the long arm of chromosome 15 occurring on the chromosome 15 inherited from the patient’s FATHER (Prader-Father). So the genomes of these patients have genetic info that derives from their mothers.
In Angelman Syndrome
chromosomal deletion of chromosome 15 inherited from MOM so you will only have genetic info from dad being expressed
Instead of a deletion, PWS can also result from
having two copies of a MATERNAL CHROMOSOME 15 (makes sense since you already are expressing only mom’s info bc you never had dad’s). Anyway this is known as maternal uniparental disomy.
Instead of a deletion, Angelman can also result from
having two copies of a PATERNAL CHROMOSOME 15 (makes sense since you already are expressing only dad’s info bc you never had mom’s to begin with)
How does uniparental isodisomy arise?
due to a non-disjunction error during meiosis leading to monosomy and trisomy
Zygote rescue rescues the monosomy
cells are able to sense that the chromosome is insufficient so they replicate the chromosome, generating uniParental isodisomy
What happens to the Trisomy
Since there are 3 chromosomes, any combination of two of them will result in uniparental heterodisomy (2 copies of the chromosome from one parent) or biparental heterodisomy (what we want-one from mom and one from dad)
t13/t14 CASE
The dad was clinically normal but he was a balanced carrier of the y13/t14 Robertsonian translocation. It turns out that the child had inherited the translocation from dad as well as the single chromosome 14: nondisjunction. Of the set of chromosomes 13 and 14, only the single 13 was from mom. This is consistent with UNIPARENTAL HETERODISOMY 14 (she got an exact complement of her dad’s chromosomes)
How did this t13/t14 arise?
nondisjunction in the father resulting in the transmission of both the translocated 13/14. This would fertilize a normal maternal gamete. Fusion results in Trisomy 14 which is compatible with life but if one of the chromosome 14 is lost then this solves the problem (zygote rescue). In this situation there is a 50/50 chance of the maternal v. paternal 14 being lost. The translocation cannot be deleted since that would result in monosomy 13. If the paternal 14 were emilinated, then a balanced chromosome complement would occur. BUT in this case the maternal 14 was lost giving rise to the chromosome complement identified by molecular analysis. Take home= still uniparental disomy
Imprinting is associated with methylation of DNA which is
epigenetic modification
Imprinting Failure
as in when a paternal imprint is transmitted but it didn’t switch from his own mom’s imprint. So instead of his child getting a paternal imprint, they will have a maternal imprint, they will have two maternal imprints
Again if you have two maternal imprints, which dz will you get?
Prader Willi (bc the dad didn’t convert his imprint from his own mom’s)
Again if you have two paternal imprints, which dz will you get?
Angelman’s bc the mom didn’t convert her imprint from her own dad’s)
What 3 things can cause Prader Willi?
- deletion of paternal chromosome
- imprinting error from MoM
- Maternal disomy
- ->opposite for Angelman’s
Normally the paternal imprint turns off
UBE3A and leaves on SNRPN and necdin. You only get one gene active, which is insufficient for normal phenotype. While mom turns off the latter two. If you have the deletion of the paternal and you only have mom active, then you will get deletions in all 3 genes==>Prader Willi
Epigenetics
mostly due to modification of transcription, which affects gene. Normal in cells. Methlyation turns genes off. X inactivation only for X-chromosome. miRNAs binds and affects translation -downregulation of miRNA can cause hyperactivity of mRNA
Uniparental Isodisomy
may result in significant abnormalities of the child but is usually undetectable by cytogenetic analysis
Uniparental isodisoly is
the inheritance of two NON-homologous chromosomes from the same parent
