39 - Genomic imprinting and epigenetics

What is the term used for reproduction using just male genetic material?

Androgenesis

What is the term used for reproduction using just female genetic material?

Parthenogenesis

What does androgenetic conception form in humans?

Hydatidiform mole

What is a hydatidiform mole?

Benign tumor of trophoblastic tissue which develops at the placenta.

If a hydatidiform mole becomes malignant what cancer is caused?

Choriocarcinoma (as a result of high levels of HCG)

How is a complete hydatidiform mole formed?

Fertilisation of an enucleated oocyte by 2 haploid sperm (46, XX)

What does parthenogenetic conception form in humans?

Ovarian teratoma

What tissues are usually seen in ovarian teratomas?

Epithelium

What 3 tissues are not seen in ovarian teratomas?

1) Skeletal muscle

2) Membranes

3) Placenta

Why do parthenogenetic embryos die?

Unable to develop extraembryonic structures such as:

- trophoblasts

- yolk sac

When do androgenetic embryos die?

6 somite stage

Why do androgenetic embryos die?

Unable to form well developed extraembryonic membranes

What is genomic imprinting?

An epigenetic phenomenon that causes genes to be expressed or not depending on whether they are maternal or paternal based of functional roles

When does genomic imprinting occur?

Gametogenesis

How many genes does genomic imprinting affect?

100-200 genes

What is the name of the imprinting abnormality characterised by a maternal deletion on chromosome 15?

Angelman syndrome

What is Angelman syndrome?

Deletion on maternal chromosome 15

Give 3 presentations associated with Angelman Syndrome:

1) Facial dysmorphism (wide mouth, smiling appearance)

2) Mental handicap (microcephaly, absent speech)

3) Ataxic, jerky movements

What is Prader-Willi syndrome?

Deletion of long arm of paternal chromosome 15

Give 4 presentations associated with Prader-Willi Syndrome:

1) Infantile hypotonia (gross motor delay, floppy limbs)

2) Mental handicap

3) Male hypogonadism (cryptochidism)

4) Hyperphagia (obesity)

Apart from chromosome 15 deletion, what is another way that Angelman and Prader-Willi Syndrome can present?

Uniparental disomy (receive only one parent's chromosome)

In order to inherit PWS by uniparental disomy, which parent's chromosomes are inherited?

Maternal chromosomes - PWS presents due to lack of active paternal genes in the PWS region. Maternal genes are inactive due to genetic imprinting

In order to inherit Angelman's syndrome by uniparental disomy, which parent's chromosomes are inherited?

Paternal chromosomes - AS presents due to lack of active maternal UBE3A genes in the AS region. Paternal genes are inactive due to genetic imprinting

What is the key mechanism of genetic imprinting?

DNA methylation

What does epigenetic mean?

Occurs outside the gene and so does not alter it

What enzyme is used to methylate DNA?

DNA methyltransferase enzymes

Is DNA methylation reversible?

Yes, but must be maintained after replication

Where on the DNA does DNA methylation occur?

CG dinucleotides - wherever these bases are found together, DNA is methylated

Does a methylated CpG island express or silence a gene?

Silence

Describe the process of expression of either a male or female gene in terms of methylation?

If a paternal allele is activated, the promoter region is unmethylated and therefore the maternal allele is methylated and so silenced

Give 3 ways that chromatin can be molecularly modified:

1) Phosphorylation

2) Methylation

3) Acetylation

Apart from methylation, what other post-transcriptional modification influences gene expression?

Histone interactions with DNA

What is the foetal-maternal growth hypothesis?

- The smaller the baby, higher incidence of perinatal mortality - so evolution favours deletion of genes that promote foetal growth

- Yet for the mother, unrestrained foetal growth brings risks to her own health

- Restraints don't apply to paternal genes

- Evolution must balance these genes

In terms of evolution, what does the expression of maternal and paternal genes present?

- Paternal genes promote foetal growth

- Maternal genes act to restrain foetal growth

What is a major growth factor involved in foetal growth?

Insulin growth factor 2 (IGF2)

What is Beckwith-Wiedemann syndrome?

- Foetal overgrowth

- Organomegaly

- Hypoglycaemia

- Asymmetry

- Tumour risk

What tumour is Beckwith-Weidwman syndrome associated with?

Wilms tumour

What is Russel-Silver syndrome?

- Foetal undergrowth

- Growth retardation

- Triangular face

What gene is affected in both Beckwith-Wiedmann and Russell-Silver syndrome?

11p15.5 (chromosome 11)

What causes Russell-Silver syndrome?

Hypomethylation causing maternal H19 to be expressed and paternal IGF2 to be under expressed

What causes Beckwith-Weidmann syndrome?

Hypermethylation causing maternal H19 to be under expressed and paternal IGF2 genes to be expressed

What is imprint switching?

The swapping of imprinting patterns between paternal alleles to erase grandparental imprints and establish a new parental input

Is X inactivation random?

Yes (random which parents X chromosome is silenced)

When does X inactivation occur?

Early embryogenesis when a blastocyst is formed

What is the name given to the split in cells with paternal vs maternal X inactivation?

Mosaicism

What is the effect of mosaicism on female carriers of X-linked mutations?

Carriers may present with a partial phenotype for the disease (skewing results in varied clinical expressions)