Imprinting and X-inactivation Flashcards
What is androgenesis?
A male is the sole source of the nuclear genetic material in the embryo.
What is parthenogenesis?
A natural form of asexual reproduction in which growth and development of embryos occur without fertilisation by sperm.
What is a hydatidiform mole?
- Results from androgenesis - normal sperm cell fertilises one of these oocytes, the resulting embryo has only one set of chromosomes (no genes from the mother)
- Mostly homoxygous 46,XX
- Proliferation of abnroaml trophoblast tissue
- No remaining embryo
What can hydatidiform moles sometimes progress into?
Malignant trohphoblastic tumour
What are ovarian teratomas?
- Parthenogenetic conceptions
- Bizarre tumor, usually benign, in the ovary that typically contains a diversity of tissues (hair teeth, bone but NO skeletal muscle)
Where are ovarian teratomas derived from?
Derived from oocytes which have completed first or both meiotic divisions - diploid
Why do parthenogenetic embryos die?
Due to failure of development of extraembryonic structures (trophoblast, yolk sac)
Why do androgenetic embryos die even though they have well developed extraembryonic membranes?
No maternal genes - poor embyro development
What is genomic imprinting?
- A mechanism that ensures the functional non-equivalence of the maternal and paternal genomes
- Not encoded in the DNA nucleotide sequence (i.e. epigenetic)
How is Angelman syndrome caused?
Most cases of Angelman syndrome are not inherited, particularly those caused by a deletion in the maternal chromosome 15 or by paternal uniparental disomy . These genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development.
What is Angelman syndrome characterised by?
- Facial dysmorphism
- Prognathism, wide mouth, drooling
- Smiling/laughing appearance
- Mental handicap
- Microcephaly
- Absent speech
- Seizure disorder
- Ataxic, jerky movements
How is Prader-Willi syndrome caused?
PWS is not generally inherited, but rather the genetic changes happen during the formation of the egg, sperm, or in early development (genetic imprinting)
Characteristics of PWS?
- Infantile hypotonia
- Feeding problems
- Gross motor delay
- Mental handicap
- Male hypogenitalism/cryptorchidism
- Small hands and feet
- Hyperphagia
- Obesity
- Stereotypic behaviour
What cytogenetic abnormality is found in both Angelman and Prader-Willi syndromes?
Deletion of chromosome 15 (always de novo):
- In Angelman, it is always the maternal chromosome 15 that carries the deletion
- In Prader-Willi, it is always the paternal chromosome 15 that carries the deletion
What is a de novo mutation?
A genetic alteration that is present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilised egg itself during early embryogenesis.
What 2 mutations are possibly involved in PWS?
- 70% deletion of chromosome 15 (paternal)
- 25% UPD (2 copies of chromosome come from mother)
I.e. in both cases there is an absence of a paternal chromosome 15
What 3 mutations are possibly involved in Angelman syndrome?
- 75% deletion chromosome 15 (maternal)
- 1% UPD (both copies of chromosome come from father)
- 2-5% point mutation (maternal)
I.e. in all cases there is an absence of materal chromosome 15
What are imprinted genes?
Imprinted genes are genes whose expression is determined by the parent that contributed them.
What is DNA methylation?
- Post-synthetic DNA modification that involves methyl groups being added to the DNA molecule
- Epigenetic: can change the activity of a DNA segment without changing the sequence
- DNA methytransferases involved
- Reversible
When is gene expression termed ‘monoallelic’?
When only one of the two copies of a gene is active, while the other is silent (imprinted genes show this).
Characteristics of BWS?
- Fetal overgrowth
- High birthweight (>5 kg)
- +/- normal adult size
- Organomegaly
- Exomphalos
- Hypoglycaemia
- Asymmetry
- Tumour risk
- Sporadic occurrence
- (Epi)genetic abnormalities
- 11p15
What is Russel-Silver syndrome?
- Growth retardation
- Fetal (IUGR)
- Persistent postnatal growth failure
- Triangular face
- Brain size more preserved
- Sporadic occurrence
What region is involved in both BWS and SRS?
Region of 11p15.5 within which the growth controlling gene insulin-like growth factor 2 is located
Describe the difference in methylation in this region of 11p15.5
These CpG-rich regions are differentially methylated on the maternally and paternally derived chromosomes:
- Methylated on paternal allele and unmethylated allele on maternal allele in normal state
- In disease state:
- SRS: both alleles epigenetically resemble the normal maternal allele (unmethylated)
- Hypomethylation –> decreased IGF2 –> SRS
-
BWS: both alleles epigenetically resemble the normal paternal allele (methylated)
- Hypermethylation –> increased IGF2 on normally silent maternal allele –> BWS
- SRS: both alleles epigenetically resemble the normal maternal allele (unmethylated)
