Genomic Imprinting Flashcards
What is genomic imprinting?
When alleles are expressed differently based on their parental origin.
Which groups does GI most commonly occur in?
Mammals and flowering plants.
How did studying human genetic disorders help us understand GI?
In disorders that involve gene deletions, the phenotype is radically different if either the maternal or paternal copy is deleted.
Which genetic disorders does deletion of the Snrpn gene on chromosome 15 cause (in humans)?
If the maternal X is deleted, Angelman syndrome results.
If the paternal X is deleted, Prader-Willi syndrome results.
What are the symptoms of Angelman syndrome?
Hyperactivity, manic laughter, repetitive movement and a large tongue
What are the symptoms of Prader-Willi syndrome?
Hypotonia, short stature and small gonads
What mechanism causes imprinting?
Acetylation or methylation as it represses transcription of a gene
Does imprinting alter the DNA molecule?
No, epigenetic markers are added/removed to alter expression patterns
Which nucleotides attract methyl groups?
CdG nucleotides (cytosines next to guanines)
Are epigenetic markers conserved during somatic cell division? Why, why not?
Yes; enzymes that recognise methylation patterns maintain them during DNA replication before cell division
Generally all DNA across a proliferating tissue carries the same epigenetic markers. What causes exceptions?
Ageing and specific tissues
What happens to epigenetic markers during gametogenesis?
They are erased and re-set depending on the sex of the organism, i.e. egg DNA displays maternal markers whilst sperm DNA displays paternal.
In autosomal genes why does imprinting occur?
Due to relatedness asymmetry among offspring in a brood.
What is the name for the relatedness asymmetry hypothesis of imprinting?
Conflict theory
Who proposed conflict theory and when?
David Haig in the 1990s
Why is there relatedness asymmetry among sibs in a brood?
Polyandry, where females mate with multiple males, means that offspring in a brood may be sired by different fathers. Therefore some are full sibs and some are half sibs.
Do offspring have the same mother?
Yes, generally.
What is the relatedness of the maternal alleles in a brood?
0.5
When taken at random from a brood in a polyandrous system, what is the relatedness of the paternal alleles?
0, as offspring more than likely have different fathers.
Why can we assume that maternal alleles act more altruistically than paternal?
Because they are more related within a brood
During feeding (in the womb), why is there conflict of interest between the mother and her offspring?
The mother wishes to save resources for herself and future offspring, whereas the offspring wish to maximise feeding for their own growth.
Why is there a cut-off point for offspring demand in feeding?
All current and future offspring share a mother and so do not want to completely deplete her.
How can Hamilton’s rule be used to explain the cut-off point in offspring demand in feeding?
rb > c
r = relatedness of sibs b = benefit to sibs c = cost to self
The cost of foregoing maximal feeding as an individual is less than the benefit of sharing resources among sibs
Why does Hamilton’s rule apply to maternal and paternal genes differently?
Because r is different.
r among maternal genes is 0.5, whilst among paternal genes it is 0.
Due to this relatedness asymmetry, what does Conflict Theory predict about the behaviour of maternal and paternal alleles in resource allocation?
Maternal alleles act altruistically to make lesser demands of the mother to save more resources for sibs.
Paternal alleles act selfishly to make more demands of the mother to take more resources for the self.
What is the outcome of conflict theory for maternal and paternal alleles?
An evolutionary arms race between them that results in the maternal allele being switched off and the paternal allele being switched on.
What evidence can be found for Conflict Theory? Who was it by and when?
Igf2 in murine systems
Haig and Graham, 1991
What is Igf2?
An embryonic growth promoter that signals to the placenta when the embryo needs feeding
When is Igf2 switched on?
When it is paternally inherited
When is Igf2 switched off?
When it is maternally inherited
How does the example in murine Igf2 support Conflict Theory?
The paternal copy of Igf2 is switched on as it acts selfishly to increase resource consumption for the self.
The maternal copy of Igf2 is switched off to act altruistically and save resources for sibs.
How was Conflict theory further supported with gene deletion experiments of Igf2 in mice?
When the paternal copy of Igf2 was deleted, the embryo displayed stunted growth.
When the maternal copy of Igf2 was deleted, the was no phenotypic effect in the embryo.
What is Igf2r?
A receptor that binds Igf2 and inhibits its growth-promoting activity
When is Igf2r switched on?
When it is maternally-inherited
When is Igf2r switched off?
When it is paternally inherited
How does the example in murine Igf2r support Conflict Theory?
The maternal copy of Igf2r is switched on to act altruistically and inhibit growth, thus saving resources for sibs.
The paternal copy of Igf2r is switched off to act selfishly and prevent the inhibition of growth, taking more resources for the self.
How was Conflict theory further supported with gene deletion experiments of Igf2r in mice?
When maternal Igf2r was deleted the embryo displayed abnormal growth.
When paternal Igf2r was deleted there was no phenotypic effect.
What happens if you delete both the Igf2 and Igf2r genes?
There is no phenotypic effect, as these genes have no other functions.
What is another name for conflict theory?
Kinship theory
Imprinted genes are usually expressed in the mammalian embryo but are also found in the brain. Who proposed that they may be involved in disorders of the social brain such as autism and psychosis?
Ubeda and Gardner, 2010
What did Ubeda and Gardner (2010) propose was the cause of genomic imprinting in social disorders?
Relatedness asymmetry caused by dispersal patterns
Explain Ubeda and Gardner’s (2010) theory? Refer to humans.
The alleles of the philopatric sex behave altruistically because they are more related to individuals in a group, causing an individual to be more sociable.
The alleles of the dispersing sex behave selfishly as they are less related to individuals in the group, causing an individual to be antisocial.
Thought that in humans, males would be altruistic and females antisocial as in ancestral humans/chimps females are dispersing sex.
Is there empirical evidence to support Ubeda and Gardner’s (2010) theory?
Why does it not work?
No, paper was purely hypothetical
Each sex has a different imprinting pattern (males are altruistic and females social), female would need to know in advance which sex offspring was going to be (male X can be selfish as always ends up in a daughter, but female Xs could be in either sex).
What is the endosperm?
The seed food store in flowering plants
What is the ploidy of a) the seed and b) the endosperm?
a) diploid
b) triploid
Why is the endosperm triploid?
It results from a whole genome duplication (WGD) of the maternal genome.
What is Meg1?
A gene that regulates resource uptake in the seed. It is expressed by the endosperm.
Is there polyandry in flowering plants?
Yes; multiple pollen grains from different fathers fertilise the mother plant, so there is relatedness asymmetry between seeds
There is relatedness asymmetry between seeds. Does Meg1 act like Igf2 by being paternally active and maternally silenced, to increase demand on the mother plant?
No; Meg1 is maternally expressed and paternally silenced.
What is the theory for why the maternal copy of Meg1 is expressed whilst the paternal copy is silenced? Refer to the triploidy of the endosperm.
There is co-adaptation between the mother and offspring. The maternal genome has more input into gene expression because of the triploid state. This ensures more resources are allocated to the zygote, producing a fitter zygote.
Maternal genome GIVES more, paternal genome silence as does not need to demand
Imprinting in autosomal genes is caused by relatedness asymmetry. What causes imprinting in X-linked genes?
Inheritance asymmetry
Who proposed inheritance asymmetry as a cause of X-linked genomic imprinting and when? What did they call their theory?
Iwasa and Pomiankowski, 1999
The Sex Specific Expression Hypothesis
X-bearing sperm are guaranteed to end up in daughters. Therefore it is suggested that they…
adopt an imprinting pattern suited to being in a female
Genomic imprinting of the X-chromosome is seen as a way of responding to sex-specific selection. Why?
Because it produces sexually-dimorphic gene expression
Explain, using the letters m and p, how X-linked imprinting causes sexually-dimorphic gene expression?
m = maternal expression (of an allele) p = paternal expression
Assuming an additive model and dosage compensation: Females = (m + p)/2 (As get an X from both parents) Males = m (As get a single maternal X)
Without imprinting, m = p
Thus females and males both end up with m expression
However imprinting means that imprinting can vary in a sex-specific way
Who looked at Turner’s syndrome in humans?
Skuse et al., 1997
What is Turner’s syndrome and why was it useful in studying genomic imprinting?
A disorder whereby human females are X0
Functions like a gene deletion experiment; effect of single X is not masked by second copy, can see phenotypic effects
What did Skuse et al. (1997) find in Turner’s syndrome sufferers if the X was maternally inherited?
Individuals were more aggressive and disruptive
What did Skuse et al. (1997) find in Turner’s syndrome sufferers if the X was paternally inherited?
Individuals displayed better social awareness
How do the results of Skuse et al.’s (1997) experiment support the Sex Specific Expression Theory?
Maternal X is aggressive; males inherit a single X from their mother and are known to be more aggressive than females
Paternal X increases social capabilities; male X guaranteed to end up in a female and females benefit from superior social cognition
Who looked at the effects of the X chromosome in X0 mice?
Thornhill and Burgoyne (1993)
What did Thornhill and Burgoyne (1993) observe in growth patterns if the X was maternally inherited?
The maternal X was growth enhancing.
What did Thornhill and Burgoyne (1993) observe in growth patterns if the X was paternally inherited?
The paternal X was growth inhibiting.
How do the results of Thornhill and Burgoyne’s (1993) experiment support the Sex Specific Expression Theory?
The maternal X is growth enhancing; males only inherit a single X from their mother and are known to have higher growth rates than females.
The paternal X is growth inhibiting; the paternal X is guaranteed to end up in a female and so inhibits growth as female (mammals) are not as big as males
In normal human females, what can be assumed about the imprinting pattern in the X chromosome with regards to the social cognition locus discovered by Skuse et al. (1997)?
The aggressive maternal allele is silenced by imprinting.
In normal female mice, what can be assumed about the growth enhancing locus on the X-chromosome described by Thornhill and Burgoyne (1993)?
The growth promoting maternal allele is silenced by imprinting.
With the inheritance asymmetry hypothesis, what does ‘imprinting’ explicitly mean in terms of gene expression?
Imprinting = silencing of the gene, e.g. ‘maternally imprinted genes’ means maternal copy is switched off
Very few genes show genomic imprinting. How many mouse genes show it?
Of the 20,000 protein-coding genes, only 1% are imprinted
Why is it strange that there are so few imprinted autosomal genes?
There are many genes involved in maternal-foetal interaction
Imprinting may be rare as methylation is a costly process. Why is this unlikely?
Because imprinting is a ubiquitous process occurring all the time throughout the genome
It has been suggested imprinting is rare because it results in monoallelic expression. Why is that a bad thing?
If a mutation occurred in a gene with monoallelic expression and disrupted gene function, there is not another copy to compensate. This would have detrimental effects on the organism.
Monoallelic expression is bad. XCI in female mammals results in monoallelic expression of the X chromosome. How does avoid the problems of monoallelic expression?
During development XCI ensures all paternal Xs are switched off.
Later in development all Xs are switched on and then one in each pair is randomly switched off.
Results in some cells expressing maternal and some paternal Xs.
If one of the Xs contains deleterious alleles, these are not expressed in ALL somatic cells and so has a smaller effect on embryo fitness.
Who reviewed GI in flowering plants?
Jiang and Kohler, 2012
Jiang and Kohler, 2012:
Why does co-adaptation theory (whereby the maternal genome is switched on and the paternal silenced in flowering plants) better explained in selfing species?
Conflict theory does not apply to selfing species because they mate with themselves, there is no conflict between the maternal and paternal genomes because they are the same thing.
Coadaptation theory ensures a fitter zygote as the doubling of the maternal genome allocates more resources to the zygote. The paternal genome does not need to be switched on to increase demand as the maternal genome gives more than normal.
Who described the gene Meg1?
Costa et al., 2012
Who described GI in flowering plants, e.g. the triploidy of the endosperm etc.?
Haig and Westoby, 1989
Why might GI have evolved? List 3 hypotheses
- Over-coming genomic conflict
- Preventing the ovarian time-bomb
- Enhanced evolvability
Who described the three hypotheses for the evolution of GI?
Wilkins and Haig, 2003
REVIEW PAPER
Wilkins and Haig, 2003
What is the ovarian time-bomb?
How does imprinting prevent the time-bomb?
Why is this argument flawed?
Ovarian trophoblastic disease; causes ovarian teratomas when an unfertilised egg spontaneously initiates development.
Paternal genes are required for teratomas to develop into invasive trophoblasts, i.e. paternal genome has active copies of genes for implantation, maternal copies are imprinted (off).
There are many imprinted genes NOT involved in trophoblast development/implantation.
Who originally described GI as the solution to the ovarian time-bomb?
Varmuza and Mann, 1994
Who originally proposed that GI caused enhanced evolvability?
McGowan and Martin, 1997
McGowan and Martin, 1997:
How does GI increase evolvability?
The functional haploidy of the imprinted gene means one allele is silenced and thus hidden from selection. Hidden alleles may have the potential to be useful in the future, therefore increasing adaptability of the organism.
Wilkins and Haig, 2003:
Why doesn’t enhanced evolvability work?
It doesn’t explain why some loci are imprinted over others, also there is a ‘patchy phylogenetic distribution’ of imprinted genes, why some taxa over others when the advantage should apply to all diploid organisms.
Which enzymes establish the methylation in imprinting?
dnmt3a and dnmt3b
Who mathematically modelled Conflict theory? What did they find?
Mochizuki et al., 1996
If there is any chance of polyandry, imprinting is favoured
Who said that the loss of monoallelic expression in GI is bad?
Morrison et al., 2005
discusses why imprinting is so rare
Who used Hamilton’s Rule as an explanation for why GI would NOT evolve?
Morrison et al., 2005
If c is great or b is small, then rb
