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1

What was shown in experiments in mice in 1984?

Both paternal and maternal genes are essential for embryo development

2

What are Gynogenetic diploids?

Injection of two female (haploid) pronuclei into a mouse egg

3

What are Androgenetic diploids?

Injection of two male (haploid) pronuclei into a mouse egg

4

what happened to the gynogenetic and androgenetic diploids?

a normal embryo did not develop in either case

5

Why did the authors conclude this was not due to the sex chromosomes?

even the XX individuals did not survive
It was down to genomic imprinting

6

How is the IGF-II signal controlled?

From paternal side

7

How is the IGF-II receptor controlled?

from the maternal side

8

What does Targeted disruption of the insulin-like growth factor II gene result in?

growth-deficient (small) mice

9

Female WT x Male heterozygote:

• Some healthy males and females
• Some small males and females (heterozygotes)
• Phenotype depends on the paternal allele they got

10

Male WT x female heterozygote:

• All offspring are phenotypically normal
• Heterozygotes of both sexes are not affected

11

What were the conclusions from the IGF-II imprinting paper?

• Transmission of the IGF-II mutation through the male germline results in heterozygous progeny that are growth deficient.
• The difference in growth phenotypes depends on the type of gamete contributing the mutated allele.
• Homozyous mutants are indistinguishable in appearance from growth-deficient heterozygous siblings
• Only the paternal allele is expressed in embryos, while the maternal allele is silent

12

What is maternal imprinting?

• Allele of a particular gene inherited from the mother is transcriptionally silent (not expressed!)
• Direct observation of the phenotype governed by the paternal allele

13

What is paternal imprinting?

• Allele of a particular gene inherited from the father is transcriptionally silent (not expressed)
• Direct observation of the phenotype governed by the maternal allele

14

What usually happens if there is a defective copy of a gene inherited?

there is a second (functioning) copy from the other parent that can compensate for this loss
not true of imprinted genes and results in disease

15

What is OMIM?

Online Mendelian Inheritance in man
It is a database for genetic diseases in humans
It is a respected source by the academic community
It is free and easy-to-understand.

16

What is the clinical phenotype of Beckwith-Wiedemann
Syndrome?

Large birth size,
Pre-disposition to tumours

17

How is Beckwith-Wiedemann
Syndrome caused?

11p15.5 (paternal)
(contains IGF-II homologue)
Hypomethylation ICR

18

What is the clinical phenotype of Prader-Willi Syndrome?

Obesity, behaviour and cognitive problems, deficiencies in sexual development

19

How is Prader-Willi Syndrome caused?

15q11-q13 (paternal)
PW region deletion (70% cases)
Maternal uniparental disomy (25% cases)
Mutations in the imprinting control region (ICR)
Translocation that separates the ICR from the Prader Willi region

20

What is the clinical phenotype of Angelman Syndrome?

Developmental deficiencies, sleep disorders, seizures, happy disposition

21

How is Angelman Syndrome caused?

15q11-q13 (maternal)
Deletion of PW region(70% cases)
Mutation of UBE3a (10%)
Paternal uniparental disomy (3%)

22

What is the clinical phenotype of Silver russell syndrome?

Growth retardation -small
triangular face
growth assymettry
immature bone development
excessive sweating
cardiac defects

23

How is Silver russell syndrome caused?

Chromosomes 7, 8, 15, 17, 18
maternal UPD
Maternal duplication of 11p15
hypomethylation of 11p15
defects in 7p11.2 and p13
encodes the GRB10 gene required for growth and development

24

What maintains and active chromatin state?

Histone acetyltransferase (HAT) targets H3 tail.
H3K14ac is a docking site for Bromo-domain
proteins;
stimulates nucleosome accessibility
Reversed by histone de-acetylases

25

What maintains a repressed chromatin state?

Histone lysine methyltransferases (KMT) methylates H3 tail.
H3K9me3 provides docking site for heterochomatin protein 1 (HP1)
Impairs nucleosome accessibility

26

What methylation state at CpG islands maintains an active state?

demethylation

27

What methylation state at CpG islands maintains a repressed state?

methylated

28

How often does epigenetic reprogramming occur in development and when?

1. During gamete formation
2. Post-fertilisation

29

What is reprogramming?

erasing and adding the epigenetic marks

30

What happens to imprinted genes during development?

• Imprinted genes always exhibit the methylation pattern of the parent in sperm or eggs regardless of whether they came from the maternal or paternal genome
• Imprinted genes bypass epigenetic reprogramming in the early embryo – not known how