Week 10

Question 1

What is imprinting?

Answer 1

The remarkable feature of imprinted genes is that both active and inactive alleles coexist in the same cell resulting in parental of origin monoallelic expression

Question 2

What are the outcomes for imprinting?

Answer 2

The imprinted allele is the silent one.
Maternally imprinted = Paternally expressed
Paternally imprinted = Maternally expressed

Question 3

What encodes for silencing of a gene?

Answer 3

Through methylation of promoters

Question 4

What genome wide imprinting effects occur when they are two male chromosome sets?

Answer 4

Embryo poorly developed
Placenta forms optimally
Yolk sac slightly smaller

Question 5

What genome wide imprinting effects occur when they are two female chromosome sets?

Answer 5

Embryo developed but slightly smaller
Placenta forms poorly
Yolk sac slightly smaller

Question 6

What genome wide imprinting effects occur when they are male and female DNA but male is added and removed?

Answer 6

All forms normally

Question 7

What happens if there are 46 male fertilisation?

Answer 7

Complete hydatidiform mole
Fertilization of enucleated oocyte by haploid sperm which duplicates or fertilization of enucleated oocyte by two sperms

Question 8

What happens if there are 46 chromosome female fertilisation?

Answer 8

Ovarian Teratoma (or dermoid cyst), 46, XX of maternal origin
Parthenogenetic conceptus

Question 9

What is an overview of imprinting evolution?

Answer 9

Imprinting is highly conserved between mammalian species and mouse
Approximately 50% of imprinted genes are conserved between human
Not found in reptiles and birds

Question 10

What is the relationship between gene location between genes that are imprinted?

Answer 10

A single ICR/DMR can influence the allelic expression for neighboring genes, often several 100kb away

Question 11

What happens to imprinting after fertilisation?

Answer 11

Zygote is demethylated by enzyme Tet3
ZFP57 and DPPA3 keep important embyo imprints present
DNA is remethylated using hemimethylated base

Question 12

What happens with the imprinting of gametes?

Answer 12

Oocyte imprinting occurs after birth
Sperm imprinting occurs before birth

Question 13

What is the reason people think imprinting may have evovled?

Answer 13

May exist due to genetic conflict
Maternally expressed genes limit growth
Paternally expressed genes enhance growth

Question 15

What are examples of male expressed genes and impact when knocked out?

Answer 15

Igf2 K/O mice are growth restricted
Pik3r1 K/O mice are growth restricted

Question 16

What are examples of female expressed genes and impact when knocked out?

Answer 16

Grb10 K/O mice show over-growth
Igf2r K/O mice show over-growth

Question 17

What non compatitve reason why imprinting evolved?

Answer 17

Most imprinted ICRs acquire DNA methylation from the oocyte.
Therefore parthenogenetic activation will be prevented in mammals due to the lack of paternally expressed genes.

Question 18

What is an overview of imprinting syndromes?

Answer 18

There are 11 known imprinting syndromes in humans.

They are associated with genetic changes:
1. Gene mutations
2. Copy-number variants (deletions and duplications)
3. Uniparental disomy
4. Epigenetic errors.
The frequency of the four types of molecular alterations varies between the different syndromes

Question 19

What is an overview of Silver-Russel syndrome?

Answer 19

Relative macrocephaly at birth, body asymmetary and feeding difficulties
1/75000 people

Question 20

WHat is an overview of Beckwith-Wiedemann syndrome?

Answer 20

Lateralised overgrowth, hernia of organs
1/15,000

Question 21

What do Silver-russel and beckwith-weidemann syndrome have in common?

Answer 21

Problems with methylation of H19 gene
SR - Hypomethylation of H19 reducing paternal expression
BW - Hypermethylation of H19 increasing maternal expression

Question 22

What is an overview of Angelman syndrome?

Answer 22

Severe intellectual disability, laughing and love of water
1/20,000 people

Question 23

What is an overview of Prader-Willi syndrome?

Answer 23

Intellectual disability, hyperphagia and obesity
1/25,000

Question 24

What do Angelman syndrome and Prader-Willi syndrome have in common?

Answer 24

Chromosome 15 deletion
AS - Removal of active allele of UBE3A
PWS - Deletion of active allele of MAGEL2 and SNORD116

Question 25

What are the percentage of commonalilty of the causes of Prader-Wili syndrome?

Answer 25

Deletion = 73%
Unitary parent disomy - 25%
Imprinting defect - 2%

Question 26

What are the percentage of commonalilty of the causes of Angelman syndrome?

Answer 26

Deletion = 73%
Unitary parent disomy - 2%
Imprinting defect - 2%
Coding mutations - 23%

Question 27

What is an overview of molecular classes of AS and PWS- gene mutations?

Answer 27

An important member of the ubiquitin-proteasome pathway.
Responsible for adding small protein molecule, ubiquitin, to proteins labelling them for degradation
Although essential for brain function, the protein targets for UEB3A are largely unknown

Question 28

What is the genotype correlations between PWS and cancer?

Answer 28

Deregulated imprinted expression implicated in childhood cancer
Increased risk of embryonal tumours, including Wilms and hepatoblastoma and adrenocortical tumours
Cancer risk depends on epigentic causes strong relation with patUPD11and H19 hypermethylation

Question 29

How have partial phenotypes been attributed to epigeentics?

Answer 29

Paternal placenta epigenetics –> causes small growth until birth but after birth the baby can catch up to normal due to epigenetics not impacting growth
Seen with DLK1 and PLAGL1

Question 30

What is an overview of genetic conflict in breast feeding?

Answer 30

GRB10 - Growth Factor Receptor Bound Protein 10
Unique in that it has two different isoforms with opposing imprinted expression
Maternally expressed in placenta, paternally expressed in neonatal brain