Imprinting And Epigenetics

Question 0

Angelman syndrome (AS)

Answer 0

Severely mentally retarded
Friendly but cannot carry on a normal conversation, inappropriate laughter
Hyperactivity, short stature, microcephaly, seizures, ataxia

Question 1

Prader-Willi syndrome (PWS)

Answer 1

Small, hypotonic at birth, but after first year begins to gain weight rapidly
Small hands, feet, hypogonadism, bad temper

Question 2

Karyotype analysis of PWS and AS

Answer 2

Microdeletion syndromes

By karyotype analysis, both appear to have same interstitial deletion of proximal long arm of chromosome 15 but clinically they are completely different

Question 3

Causes of PWS and AS

Answer 3

PWS:
deletion present on chromosome 15 inherited from dad (only maternal alleles)
Maternal uniparental disomy
Imprinting error where complement is comprised of one chromosome from dad and one from mom but paternal chromosome has a material imprint resulting in only maternal functional alleles

AS: opposite of PWS

Question 4

Uniparental disomy (UPD)

Answer 4

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

Question 5

UPD can be heterodisomy or isodisomy

Answer 5

Need to use molecular studies to distinguish because they look the same

Heterodisomy: chromosomes are from different sources (distinct alleles)

Isodisomy: chromosomes are duplicate copies (same alleles)

Question 6

Biparental heterodisomy

Answer 6

1 chromosome from each parent

This is expected pattern

Question 7

Uniparental isodisomy

Answer 7

Nondisjunction error can give rise to a trisomy or a monosomy

Mechanism of rescue for monosomy is duplication of the chromosome which will generate uniparental isodisomy

Question 8

Uniparental heterodisomy

Answer 8

Nondisjunction error can give rise to a trisomy or a monosomy

Loss of one chromosome is usually random in the trisomy

2/3 of the time the outcome will be Biparental heterodisomy but 1/3 results in uniparental heterodisomy (2 different copies of chromosome from same parent)

Question 9

Imprinting

Answer 9

Differential modification of the maternal and paternal genetic contributions to the zygote resulting in the differential expression of parental alleles during development and in the adult

PWS and AS=genetic imprinting

Question 10

Male vs female effect in imprinting

Answer 10

For some genes or chromosomal regions, may be important to have maternal and paternal contribution

Lasts one generation

Change occurs during meiosis (human somatic cells are mosaics of male and female imprinted chromosomes but during reproduction, these chromosomes need to be modified into correct imprint to be transmitted to offspring so they will get equal allotment of male and female chromosomes, male must give “male” chromosome, female must give “female” chromosome)

Usually associated with methylation (addition of methyl groups to cytosine residues in DNA usually for inactivation)

Question 11

Differences in parental imprints

Answer 11

Maternal: genes SNRPN and nectin are inactive but UBE3A is active

Paternal: gene UBE3A is inactive and SNRPN and nectin are active

All genes are active when maternal and paternal together

Question 12

Epigenetic modifications

Answer 12

DNA methylation (x-inactivation, methylation)

Histone modification: position of nucleosomes

Chromatin remodeling

Question 13

Malfunction of epigenetic factors

Answer 13

Hypo methylation can result in over expression of genes like proto-oncogenes

Hyper methylation can inactivate necessary regulatory genes like tumor suppressor genes

Question 14

MicroRNA (miRNA)

Answer 14

Small, non coding RNAs
Bind to mRNA to regulate gene expression
Down regulation of miRNA caused by hyper methylation at miRNA promotors results in tumors