Imprinted genes in mammals Flashcards
What was the earliest indication that maternal and paternal genes are not equivalent?
The mule and hinny.
Horse (mare) and Donkey (jack) = Mule
Donkey (jenny) and Horse (stallion) = Hinny
Hinny has bad temperment and less well suited to domestication than a reliable mule
Give another example of maternal and paternal genes not eqivalent.
Liger = Male lion and female tiger.
Tigon = Male tiger and female lion.
Males are sterile and on ocasion females can produce offspring.
Why might ligers be larger and heavier?
Ligers tend to be larger and heavier than members of their parentspecies. Biologists suggest that the liger’s large size, or “growth dysplasia,” results from the absence of certain growth-limitinggenes.
Whats the hypothesis that ligers are large?
Female lions mate with several male lions throughout their lives, so the genes of a male lion are adapted to maximize the growth of his offspring, since his offspring may be required to compete with those of other males produced by the same lioness.
The genes of female lions, however, are adapted to cancel or dampen the effects of the growth-maximizing genes of male lions, so lions remain within a given size range.
Tigers, on the other hand, have no such competitive mating strategy, and many biologists argue that tigresses do not possess the growth-limitingadaptationsof their lioness counterparts.
As a result, the influence of the growth-maximizing adaptations provided by male lions is greater, which allows ligers to become larger than their parents.
Why are tigons only slighter larger than their parents?
For tigons, growth-limiting genes are found in both male tigers and female lions, so their offspring possess an abundance of these genes, which accounts for their smaller size.
What do vast majority of genes in parental genomes do?
Cooperate to make a healthy human.
What is essential for embryo development?
Both paternal and maternal genes.
Where did the first evidence of genomic imprinting come from?
Two studies in mice. (see slide diagram)
Surani,M.A et. al. Nature 308, 548–550 (1984).
McGrath and Solter (1984)
Describe the experiment which led to the finding of genomic imprinting
Gynogenetic diploids
Infection of two female (haploid) pronuclei into a mouse egg
Androgenetic diploids
Injection of two male (haploid) pronuclei into a mouse egg
What was the outcome of this experiment which discovered genomic imprinting?
Even though both egg cells now contain a ‘diploid’ level of DNA, a normal embryo did not develop in either case.
As even the XX individuals did not survive, the authors concluded that this could not be due to the sex chromosomes.
Control embryos from a paternally-derived pronucleus and maternally-derived pronucleus developed normally when transferred into a foster mother.
It was down to genomic imprinting
What is imprinting essential for?
Normal development in mammals.
Whats an classic example of genomic imprinting
Maternal imprinting of IGF-II in mice.
DeChiara et al Cell (1992)
DeChiara et al Cell (1992)
Targeted knockout of the insulin-like growth factor II gene results in growth-deficient (small) mice.
Heterozygotes of both sexes* are small
*This is not a sex-linked trait (IGF II is on chromosome 7)
Heterozygotes of both sexes* normal size
What is the explanation of results of this experiment testing imprinting of IGF-II in mice. ?
The maternal copy is silenced.
So if you have a mini-mum and a regular-sized Dad, you are a regular sized mouse. Mini-Dad; Regular mum you are a mini mouse. This is because the phenotype is controlled only by the paternal copy.
(partial_ pedigree if IGF2 mutant animals
What was in situ hybridisation used to show?
Went on to show that only the paternal gene is expressed in the developing embryo.
Conclusions from IGF-II imprinting paper
Transmission of the IGF-II mutation through the male germline results in heterozygous progeny that are growth deficient.
When the disrupted gene is transmitted maternally, the heterozygous off-spring are phenotypically normal.
The difference in growth phenotypes depends on the type of gamete contributing the mutated allele.
Homozyous mutants are indistinguishable in appearance from growth-deficient heterozygous siblings
Only the paternal allele is expressed in embryos, while the maternal allele is silent
Key findings from the imprinting paper
In mice the paternal and maternal members of some autosomal gene pairs are functionally non-equivalent.
The IGF-II locus has since been studied in great detail and a lot of our current knowledge comes from manipulation of this system
What do nuclease protection and in situ hybridisation analyses of the transcripts from the wild-type and mutated alleles indicate?
That only the paternal allele is expressed in embryos, while the maternal allele is silent.
WHat is this now a model of?
This is now a model for studying imprinting – most of the molecular details of imprinting in mammals is based on mouse studies
mice that carry a targeted disruption of the gene encoding insulin-like growth factor II (IGF- II).
What do chromatin states govern?
Gene activity.
Euchromatin and heterochromatin.
Activate state of chromatin
Histone acetylation by HAT (p55)
Histone acetyl-transferase (HAT) targets H3 tail.
H3K14ac is a docking site for Bromo-domain proteins
Stimulates nucleosome accessibility and transcriptional activity.
