L14- Genome Imprinting

Question 1

What is parthenogenesis

Answer 1

oocytes which have completed first or both meiotic divisions

No sperm

46, XX

Question 2

What is Androgenesis

Answer 2

Sperm enters oocyte (oocyte with no DNA) and then sperm divides

46, XX

Question 3

Hyaditiform mole

Answer 3

-Androgenetic
Complete hydatidiform moles
Mostly homozygous 46,XX
Proliferation of abnormal trophoblast tissue

Can develop into malignant trophoblastic tumour
No (remaining) embryo

Question 4

Parthenogenesis

Answer 4

Benign ovarian teratomas

-Derived from oocytes which have completed first or both -meiotic divisions
    Diploid
    Wide spectrum of tissues
    Predominantly epithelial
    No skeletal muscle   
    No membranes/placenta

Question 5

Parthenogenetic embryos die due to…?

Answer 5

Failure of development of extraembryonic structures

• Trophoblast
• Yolk sac

(paternally expressed genes tend to be growth promoting whereas maternally expressed genes tend to be growth limiting)

Question 6

Why do Androgenetic embryos die at 6 somite stage

Answer 6

They have Well developed extra-embryonic membranes but Poor embryo development

Question 7

Concept of genomic imprinting and what is it? (hard one!)

Answer 7

Mothers and fathers somehow “imprint” their genes with a memory of their paternal or maternal origin

A mechanism that ensures the functional non-equivalence of the maternal and paternal genomes

Not encoded in the DNA nucleotide sequence
i.e. epigenetic

Depends on modifications to the genome laid down during gametogenesis
-Spermatogenesis vs. oogenesis

Affects the expression of a small subset of 100-200 genes
Evolutionarily conserved

Clinical consequences

Question 8

Angelman syndrome

Answer 8

-Facial dysmorphism
Prognathism, wide mouth, drooling
Smiling/laughing appearance
-Mental handicap
Microcephaly
Absent speech

Seizure disorder
Ataxic, jerky movements

Angelman 1965
“puppet children”

Bower & Jeavons 1967
“happy puppet”

Question 9

Prader-Willi syndrome

Answer 9

Infantile hypotonia

• Feeding problems
• Gross motor delay

Mental handicap
Male hypogenitalism/cryptorchidism
Small hands and feet

Hyperphagia
-Obesity

Stereotypic behaviour

Question 10

Cytogenetic abnormalities in Angelman syndrome and Prader-Willi syndrome

Answer 10

Deletion of chromosome 15
Found in both Angelman and Prader-Willi syndromes

Always de novo
-Recurrence risks very low

Question 11

What is DNA methylation?

Answer 11

Post-synthetic DNA modification

Epigenetic
-Does not normally alter DNA sequence

DNA methyltransferases
Reversible
Has to be “maintained” after replication
Occurs at CG dinucleotides
Many promoter regions spared
-CG “islands”
-Gene regulation

Question 12

Do Imprinted genes show mono allelic expression?

Answer 12

Yes, Epigenetic differences between maternal and paternal copy (allele)….only one will be activated

Question 13

IGF2 and Russell-Silver syndrome

Answer 13

Hypomethylation –> decreased IGF2 –> SRS
If IGF maternal and paternal genes are off
One needed to be on for it to be normal

Question 14

IGF2 and Beckwith-Wiedemann syndrome

Answer 14

Hypermethylation –> increased IGF2 –> BWS
If both maternal and paternal genes for IGF2 are on
One needed to be on for it to be normal

Question 15

Russell-Silver syndrome

Answer 15

Growth retardation
-Fetal (IUGR) 
-Persistent postnatal growth failure
Triangular face
-Brain size more preserved
Asymmetry
Sporadic occurrence

Question 16

Beckwith-Wiedemann syndrome

Answer 16

Fetal overgrowth
-High birthweight (>5 kg)
+/- normal adult size

Organomegaly
-Exomphalos

Hypoglycaemia
Asymmetry
Tumour risk
Sporadic occurrence

(Epi)genetic abnormalities
-11p15

Question 17

Imprint “switching”

Answer 17

Imprinting must be “remembered” during somatic development

“Forgotten” before gametogenesis (it is reset during gametogenesis)

Question 18

Summary of genomic imprinting

Answer 18

Genomic imprinting regulates the activity of a small subset of human genes

• Affects inheritance pattern of some clinical disorders
• May have a role in tumorigenesis

Correct imprinting is required for normal growth and development

Question 19

How can male and female cells ensure equivalent dosage of genes (number of copies of a particular gene present in a genome) located on Chr. X?

Answer 19

In females, monoallelic expression is needed

• Achieved by epigenetic silencing
• Somatic cells remember silenced status
• Reversed in germ cells

X inactivation

Question 20

X inactivation

Answer 20

Whole X chromosome is silenced

• Random choice of parental chromosome
• Different in different cells
• Somatic cell clones “remember”

Occurs early in embryogenesis
-Blastocyst

Carriers of X-linked mutations have some functionally defective and some normal cells

Question 21

Hypohidrotic ectodermal dysplasia

Answer 21

X-linked mutation

Patches of skin with or without sweat glands