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What was shown in experiments in mice in 1984?

Both paternal and maternal genes are essential for embryo development


What are Gynogenetic diploids?

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


What are Androgenetic diploids?

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


what happened to the gynogenetic and androgenetic diploids?

a normal embryo did not develop in either case


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


How is the IGF-II signal controlled?

From paternal side


How is the IGF-II receptor controlled?

from the maternal side


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

growth-deficient (small) mice


Female WT x Male heterozygote:

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


Male WT x female heterozygote:

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


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


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


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


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


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.


What is the clinical phenotype of Beckwith-Wiedemann

Large birth size,
Pre-disposition to tumours


How is Beckwith-Wiedemann
Syndrome caused?

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


What is the clinical phenotype of Prader-Willi Syndrome?

Obesity, behaviour and cognitive problems, deficiencies in sexual development


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


What is the clinical phenotype of Angelman Syndrome?

Developmental deficiencies, sleep disorders, seizures, happy disposition


How is Angelman Syndrome caused?

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


What is the clinical phenotype of Silver russell syndrome?

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


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


What maintains and active chromatin state?

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


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


What methylation state at CpG islands maintains an active state?



What methylation state at CpG islands maintains a repressed state?



How often does epigenetic reprogramming occur in development and when?

1. During gamete formation
2. Post-fertilisation


What is reprogramming?

erasing and adding the epigenetic marks


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