Genomic imprinting

Question 1

How was imprinting discovered?

Answer 1

Through uniparental embryos and uniparental disomy.
Uniparental embryos: parthenogenetic (PG - maternal) or androgenetic (AG - paternal).
PG –> fully formed fetus (but small), extra embryonic tissues (yolk sac, trophectoderm) don’t form well
AG –> opposite

Question 2

Why does imprinting occur (2 hypotheses)

Answer 2

Parental conflict hypothesis - evolved as result of conflicting interests between maternal and paternal genes. Imprinted genes thought to influence transfer of nutrients. Maternal tend to conserve resources, divide between more offspring etc. Paternal tend to extract more.

Coadaptation hypothesis - Relevant to subset of paternal genes which are expressed in both placenta and hypothalamus. Based on idea that doesn’t matter whether genes are maternal or paternal, it’s whether they lead to best interests of offpsring. I.e. gene can act coadaptively to affect offspring directly and mother (maternal behaviour etc).

Question 3

Igf2

Answer 3

Insulin-like growth factor 2.
One of the first imprinted genes discovered. Important in development and brain function.
Paternal imprint encodes Igf2 (key in placental development, promotes foetal growth, extracts resources).
Maternal imprint encodes its receptor. When the two bind, IGF2 is destroyed, reducing its effects on growth.

Question 4

Imprinted gene clusters

Answer 4

Most imprinted genes clustered together, each cluster contains 2-15 genes. Contain both maternal and paternal genes. Parent-specific expression of multiple genes in a cluster is under control of the ICR (imprinting control region), active when unmethylated.

Question 5

Transcription/No transcription

Answer 5

Imprinted genes are methylated and deacetylated –> condensation of the nucleosome, transcription machinery can’t access.

Transcriptionally competent genes are demethylated and acetylated.

Question 6

Mechanism of methylation

Answer 6

DNA methyltransferases cause methylation.

Dnmt1 –> MAINTAIN methylation (hemi-methylated –> fully methylated) (from zygote onwards - when somatic cells divide)

Dnmt3a and 3b –> DE NOVO methylation (sperm/oocyte)

In gonad, get erasure (genome wide demethylation of germ cells)

Question 7

Chimaera studies

Answer 7

AG/PG embryos don’t survive so need to use chimaera by adding normal cells (less than 40% AG/PG for survival)
PG-N(normal) –> large brain, small body, increased aggression in males
AG-N –> small brain, large body
Suggests maternal/paternal genes allocate resources differently to brain and body development.
PG-derived cells also go more into cortical regions whereas AG go to hypothalamus and preoptic area, suggesting maternal/paternal genes have different effects on brain development and function

Question 8

PEG3

Answer 8

Paternally expressed gene 3
Expressed in placenta, maternal hypothalamus and foetal hypothalamus. Regulates maternal behaviour and physiology (care, milk release, newborn suckling).

Question 9

Peg3 KO

Answer 9

Take longer to retrieve pups, longer to make nests, longer to adopt crouching position for suckling.
Progeny –> slower growth
This can be a result of the mother being a KO or the pups being a KO.
If mother is a KO, gene isn’t expressed in her hypothalamus (so impaired maternal care) but is still expressed in foetus and placenta.
If pup is a KO, gene isn’t expressed in pup hypothalamus or placenta (so impaired placental growth etc.), but still expressed in mother’s hypothalamus.
Demonstrates FUNCTIONAL COADAPTATION of Peg3.

Question 10

What does Peg3 do in males?

Answer 10

Increases chances of finding a fertile female 80-fold. Rat ovarian cycle only 4 days, receptive during one day (female pheromones produced in urine at this time)

Question 11

Turner syndrome (how it happens, cognitive features, study)

Answer 11

Happens randomly at conception due to non-disjunction in gamete formation. X can come from mother or father, but 70% mother.

Ovarian failure occurs in the fetus, which affects neurodevelopment. Impaired attention, working memory, abstract reasoning. Moderate social impairments (non-verbal cues etc.)

Cognitive features are likely X-linked. More likely if X is maternal. Study looking at social cognition showed they score higher (worse) than WT boys and girls, particularly if X is maternal. Concluded some genes involved in cog. social skills are paternally imprinted - in maternal X these genes are silenced.

X-linked disorders have higher rates of autism.