Imprinting and Epigenetics Flashcards
Where is the defect found in Angelman and Prader-Willi syndrome?
Interstitial deletion of proximal long arm of chromosome 15 (q)
How effective are FISH in detecting Angelman and Prader-Willi? What is left as “unknown?”
65-85%; meaning that 15-35% of cases are left as unknown
Where is the deletion in Prader-Willi, M or P? Angelman, M or P?
P 15q; M 15q
What is sometimes seen in PWS and AS patients instead of deletions? Which parent’s chromosomes would we see in either case?
Uniparental disomy (UPD); maternal in case of PWS, paternal in case of AS
Define uniparental disomy
Inheritance of a chromosome or chromosomes from 1 parent to exclusion of the other
Can you detect UPD by karyotype analysis? Why?
No; homologs will look alike
What is biparental heterodisomy? Uniparental heterodisomy? Uniparental isodisomy?
What we want: one chromosome given by each parent;
one parent gives his/her homologous chromosomes;
one parent gives one chromosome that’s been duplicated
Although rare, how could one get uniparental isodisomy?
Through a nondisjunction error, resulting in monosomy that is rescued by “zygote rescue,” where the chromosome is duplicated resulting in uniparental isodisomy!!
For two parents, one of whom is a carrier of CF, can the child have CF? Why?
Yes; uniparental isodisomy where the child’s chromosomes would be identical and from the carrier parent
How could biparental heterodisomy emerge? Uniparental heterodisomy?
From the nondisjunction error: in the case of the trisomic gamete, one of the chromosomes could be lost, resulting in biparental heterodisomy, which is what we want;
other case is uniparental heterodisomy (happens 1/3 of the time)
What is imprinting?
Differential mod of the M and P genetic contributions to the zygote, leading to differential expression of parental alleles during development and in adulthood
What might need both a maternal and paternal contribution? What is an epigenetic modification?
Certain regions and chromosomal regions;
methylation
Where does one methylate in the DNA? Where can methylation occur?
Cytosine residues; can occur in single gene, group of close genes, portion of a single chromosome, over full length of one or more chromosomes!!!
How long does imprinting last? When do you make changes?
One generation; at meiosis (e.g. X-inactivation)
What will a male pass on in terms of chromosomes? Females? What is one of the functions of meiosis with respect to chromosomes ending up as gametes?
Male imprinted (methylated) chromosomes; female imprinted chromosomes; Reimprint the chromosomes, so male meiosis will have imprint from mom stripped and replaced with male imprint (methylation pattern)
Is it possible to have biparental disomy and still result in something like PWS?
Yes; the father’s chromosome passed down did not reimprint and still had the mother’s imprinting even after meiosis;
What three mech’s could PWS thus be due to?
- deletion of paternal chromosome 15
- Maternal UPD (maternally imprinted chromosomes)
- Imprinting error (biparental heterodisomy but failure of paternal chromosome to imprint during meiosis)
What three mech’s could AS be due to?
Same as 3 basically, but paternal UPD and also failure of maternal imprinting
What can FISH detect for PWS and AW mostly? What percent of PWS cases are UPD? What accounts for a significant chunk of problems seen with AS?
Deletions on chromosome 15; 15-20%
25% are mutations due to UBE3A gene
In normal cases, what genes are active on paternal chromosome vs. maternal chromosome? What happens in PWS? What happens in AS?
SNRPN and necdin on paternal, UBE3A on maternal;
PWS will only have the maternal imprints (UBE3A);
AS will only have the paternal imprints (SNRPN and necdin)
What is imprinting very important for?
Development early on in the zygote
What is epigenetics? What is modified? What can happen with changes in epigenetic effects?
Study of heritable changes in gene function NOT due to DNA sequence changes; transcription, altering gene expression and phenotype; up- or down-regulation of genes
What are three categories of epigenetic modification?
DNA methylation, histone modification, chromatin remodeling
What must happen with respect to genes in order to create specific tissue and organ phenotype?
A specific pattern of genes must be active, and other inactivated
What can methylation of DNA act as?
Transcription repressor by blocking cofactor and activator binding
What does a nucleosome consist of? What type of methylated DNA usually? Which type of DNA is open to transcription?
Histones and DNA; condensed DNA; unmethylated DNA without histones
What can miRNAs function as? What can downregulate miRNA? What would this lead to? What are some examples of diseases linked with downregulated miRNA?
regulate gene expression and prevent/interfere with translation; hypermethylation of miRNA promoters; tumors; leukemia, Alzheimer’s, breast cancer
Who does Rett syndrome primarily affect? What are some symptoms; what is the gene affected? what is disease severity linked to and what could lead to a milder phenotype?
Females; disruption of motor function, intellectual disability, loss of speech, seizures;
MECP2;
patient more severely affected if mutation is found on the active X chromosome, but less severe if on the inactive X
