Imprinting and Epigenetics

Question 1

Where is the defect found in Angelman and Prader-Willi syndrome?

Answer 1

Interstitial deletion of proximal long arm of chromosome 15 (q)

Question 2

How effective are FISH in detecting Angelman and Prader-Willi? What is left as “unknown?”

Answer 2

65-85%; meaning that 15-35% of cases are left as unknown

Question 3

Where is the deletion in Prader-Willi, M or P? Angelman, M or P?

Answer 3

P 15q; M 15q

Question 4

What is sometimes seen in PWS and AS patients instead of deletions? Which parent’s chromosomes would we see in either case?

Answer 4

Uniparental disomy (UPD); maternal in case of PWS, paternal in case of AS

Question 5

Define uniparental disomy

Answer 5

Inheritance of a chromosome or chromosomes from 1 parent to exclusion of the other

Question 6

Can you detect UPD by karyotype analysis? Why?

Answer 6

No; homologs will look alike

Question 7

What is biparental heterodisomy? Uniparental heterodisomy? Uniparental isodisomy?

Answer 7

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

Question 8

Although rare, how could one get uniparental isodisomy?

Answer 8

Through a nondisjunction error, resulting in monosomy that is rescued by “zygote rescue,” where the chromosome is duplicated resulting in uniparental isodisomy!!

Question 9

For two parents, one of whom is a carrier of CF, can the child have CF? Why?

Answer 9

Yes; uniparental isodisomy where the child’s chromosomes would be identical and from the carrier parent

Question 10

How could biparental heterodisomy emerge? Uniparental heterodisomy?

Answer 10

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)

Question 11

What is imprinting?

Answer 11

Differential mod of the M and P genetic contributions to the zygote, leading to differential expression of parental alleles during development and in adulthood

Question 12

What might need both a maternal and paternal contribution? What is an epigenetic modification?

Answer 12

Certain regions and chromosomal regions;

methylation

Question 13

Where does one methylate in the DNA? Where can methylation occur?

Answer 13

Cytosine residues; can occur in single gene, group of close genes, portion of a single chromosome, over full length of one or more chromosomes!!!

Question 14

How long does imprinting last? When do you make changes?

Answer 14

One generation; at meiosis (e.g. X-inactivation)

Question 15

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?

Answer 15

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)

Question 16

Is it possible to have biparental disomy and still result in something like PWS?

Answer 16

Yes; the father’s chromosome passed down did not reimprint and still had the mother’s imprinting even after meiosis;

Question 17

What three mech’s could PWS thus be due to?

Answer 17

1. deletion of paternal chromosome 15
2. Maternal UPD (maternally imprinted chromosomes)
3. Imprinting error (biparental heterodisomy but failure of paternal chromosome to imprint during meiosis)

Question 18

What three mech’s could AS be due to?

Answer 18

Same as 3 basically, but paternal UPD and also failure of maternal imprinting

Question 19

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?

Answer 19

Deletions on chromosome 15; 15-20%

25% are mutations due to UBE3A gene

Question 20

In normal cases, what genes are active on paternal chromosome vs. maternal chromosome? What happens in PWS? What happens in AS?

Answer 20

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)

Question 21

What is imprinting very important for?

Answer 21

Development early on in the zygote

Question 22

What is epigenetics? What is modified? What can happen with changes in epigenetic effects?

Answer 22

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

Question 23

What are three categories of epigenetic modification?

Answer 23

DNA methylation, histone modification, chromatin remodeling

Question 24

What must happen with respect to genes in order to create specific tissue and organ phenotype?

Answer 24

A specific pattern of genes must be active, and other inactivated

Question 25

What can methylation of DNA act as?

Answer 25

Transcription repressor by blocking cofactor and activator binding

Question 26

What does a nucleosome consist of? What type of methylated DNA usually? Which type of DNA is open to transcription?

Answer 26

Histones and DNA; condensed DNA; unmethylated DNA without histones

Question 27

What can miRNAs function as? What can downregulate miRNA? What would this lead to? What are some examples of diseases linked with downregulated miRNA?

Answer 27

regulate gene expression and prevent/interfere with translation; hypermethylation of miRNA promoters; tumors; leukemia, Alzheimer’s, breast cancer

Question 28

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?

Answer 28

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