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Genomic Imprinting

Genomic Imprinting. Tradeoffs in communication between maternal and paternal genetic effects. Genomic Imprinting. Differential expression of genes depending on parental inheritance Imprints – epigenetic instructions laid down in the parental germ cells

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Genomic Imprinting

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  1. Genomic Imprinting Tradeoffs in communication between maternal and paternal genetic effects

  2. Genomic Imprinting Differential expression of genes depending on parental inheritance • Imprints – epigenetic instructions laid down in the parental germ cells • Transfer of nutrients from mother to fetus • Genetic disorders

  3. Evidence • Uniparental embryos • Uniparental disomy • Differences in maternal and paternal gene function

  4. How does imprinting work? • DNA methylation • differentially methylated regions (DMRs) • Imprinting centers or imprinting control elements (ICs)

  5. How does imprinting work?

  6. Methylation and Expression

  7. Life Cycle of an Imprint

  8. Evolution • Found in eutherian mammals, marsupials, and flowering plants • 45 imprinted genes in mouse • Maternal resources • maternal-paternal conflicts • arms races?

  9. Imprinting andSignal Detection Theory • Maternal-offspring communication • conflicts • deception/exploitation • countermeasures

  10. Phenotypic effects • In utero effects • Insulin and insulin-like growth factors • Placental growth • Postnatal effects • Hyperkinetic/hypokinetic • Lactation? • Brain development and function

  11. Genetic Disorders • Epimutations • Prader-Willi syndrome • Angelman syndrome

  12. Experiments • Jena: Costs to the mother in expression of the imprinted gene Pref1 • Jun: Test for polymorphism in imprinted genes • Tim: Uses of genomic imprinting for medical diagnoses of neurobehavioral disorders

  13. Introduction • Preadipocyte factor 1 (Pref-1) • adipogenesis – differentiation of fat cells • Functions as a pre-natal growth regulator

  14. Relation to Genomic Imprinting • Paternally expressed • Arms Race • Based on phenotypic expression • i.e. size

  15. Hypothesis There is a cost to the mother associated with the expression of Pref-1.

  16. Experimental Design • Wild-type (+/+) vs. null (+/-) • Use of knock-out mice • Differences in size • Small = beneficial for mom • Large = beneficial for dad • Resource use

  17. Potential Outcomes • If cost is found • This supports Arms Race Theory • If neutral or beneficial • Further research is warranted

  18. The Expression Profiles of IGF2 in the vetebrate animals Test the theory of arm race “tug-of-war” between IGF2 and IGF2R

  19. Background for the experiment • The IGF2 and M6P/IGF2R were the first two endogenous genes which contribute embryonic growth. • IGF2: paternal, pro-growth; IGF2R: maternal, anti-growth • IGF2 signaling is not mediated by M6P/IGF2P, but IGF1 receptor or insulin receptor • The reciprocal imprinting of the two genes show “ tug-of-war” • 80% genes are physically linked in the cluster on some chromosomes. • The functions and linkage of the two genes suggest that there is co-evolution. “arm race”?

  20. The evolution of the genomic imprinting gene IGF2R • The gene was found only in the eutherian, marsupial but not monotremes • The IGF2R/M6P shows polymorphism • IGF2R binding ability to IGF2 mammalian: +++++, marsupial: +, monotremes:- Molecular cell, 2000, 5:707-716

  21. Experiment Design • Choosing the animals • IGF2 Polymorphism detecting • Gene expression profiles of IGF2 and M6P/IGF2R • Gene sequence compare and analysis • Epimutate the two genes to test their interaction • Test the coevolution theory: arm race

  22. Choosing the animals According the evolutionary history: • invetebrate • Monotremes • Marsupial • eutherial

  23. Polymorphism and expression profile detecting • RT-PCR: reverse transciption PCR • SNP: single-nucleotide polymorphism • Western Bolt

  24. Gene sequence compare and analysis • Cloning and sequencing • Phylogenetic analysis • Functional domain and binding domain prediction: try to give an explanation for the change of the binding ability

  25. Epimutation Analysis • To test their interaction • Change the methylation or chromatin pattern • Interaction? IGF2(P) M6P/IGF2R (M) IGF2(P) M6P/IGF2R (P) IGF2(M) M6P/IGF2R (M) IGF2(M) M6P/IGF2R (P)

  26. Test the theory “tug-of-war” between IGF2 and IGF2R

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