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RNA ..the fourth dimension in evolution....

RNA ..the fourth dimension in evolution. ...or how nurture could influence nature. descent with modification by means of natural selection - Darwin’s big idea requires that:. 1) characteristics of a living organism – the phenotype – are heritable.

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RNA ..the fourth dimension in evolution....

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  1. RNA ..the fourth dimension in evolution.... ...or how nurture could influence nature

  2. descent with modification by means of natural selection - Darwin’s big idea requires that: 1) characteristics of a living organism – the phenotype – are heritable

  3. descent with modification by means of natural selection - Darwin’s big idea requires that: 2) there is variation in heritable phenotypes What Henslow taught Darwin: How a herbarium helped to lay the foundations of evolutionary thinking. David Kohn, Gina Murrell, John Parker and Mark Whitehorn Nature (2005) vol 436 pp 643-645

  4. heritability requires information storage and transmission • the first dimension – genetic information storage • a second dimension – behaviour • a third dimension – symbolism • a fourth dimension ……

  5. transgenerational epigenetic effects in plants Manning, K. et al. A naturally occurring epigenetic mutation in a gene encoding an SBP-box transcription factor inhibits tomato fruit ripening. Nat Genet38, 948-952 (2006). Cubas, P., Vincent, C. & Coen, E. An epigenetic mutation responsible for natural variation in floral symmetry. Nature401, 157-161 (1999).

  6. epimutations can be induced and targeted B’ B-I Paramutation vocabulary B’ is paramutagenic B-I is paramutable B-I paramutates to B’* B’ and B’* are indistinguishable and paramutagenic B’*

  7. RNA virus-induced epimutation RdRP RdRP RdRP m m m st st st CP CP CP 35S GF virus vector constructs host plant genotype cod pro cod NB under UV light plants are red (chlorophyll) unless they express green fluorescent protein (GFP) pro

  8. viral RNA induces a specific and heritable epimutation RdRP RdRP RdRP m m m st st st progeny CP CP CP 35S GF no silencing non heritable silencing heritable silencing cod virus vector constructs infected plants pro Jones, L., F. Ratcliff, and D.C. Baulcombe, (2001) RNA-directed transcriptional gene silencing in plants can be inherited independently of the RNA trigger and requires Met1 for maintenance. Current Biology, 2001. 11: p. 747-757.

  9. RdRP m st CP 35S DNA replication mitosis/meiosis IIIIII IIIIII IIIIII cod pro cod pro DNA DNA initiation (does not require MET1) maintenance (requires MET1) separate initiation and maintenance in heritable epimutation RNA pro cod pro DNA

  10. distorting the central dogma of molecular biology

  11. … the fourth dimension • evolution requires variation in heritable traits • heritable variation can be achieved other than by genetic mutation – epimutation • epimutations differ from genetic mutations in that they may be unstable and in that they can be induced and targeted • RNA can initiate variation that is inherited by mechanisms that are independent of RNA

  12. mechanisms – the two phases of epimutation initiation – targeted de novo DNA methylation by de novo DNA methyltransferase maintenance – addition of methyl groups to newly replicated DNA at sites of methylation in parent strand – maintenance methylase

  13. DNA methylation results in gene silencing atlasgeneticsoncology.org/Educ/HeterochromEng...

  14. ssRNA RdRP(RDR) RDR6 knock down wt mechanisms – the role of RNARNA silencing of RNA dsDNA PolIV dsRNA dicer 21+24nt small RNA – small interfering RNA uses small interfering RNA as a guide argonaut slicer

  15. ssRNA RdRP(RDR) mechanisms – the role of RNARNA silencing of RNA dsDNA PolIV dsRNA dicer argonaut slicer

  16. ssRNA RdRP(RDR) mechanisms – the role of RNARNA silencing of DNA dsDNA PolIV dsRNA DNMT dicer 21+24nt small RNA – small interfering RNA uses small interfering RNA as a guide argonaut slicer

  17. ssRNA RdRP(RDR) mechanisms – the role of RNARNA silencing of DNA dsDNA PolIV IIIIIIIII dsRNA DNMT dicer 21+24nt small RNA – small interfering RNA uses small interfering RNA as a guide argonaut slicer

  18. MPSS – 17 nt read – no length data Elucidation of the Small RNA Component of the Transcriptome. Lu, C., S. S. Tej, et al. Science (2005) 309: 1567 454 – mechanical cloning – pyrosequencing Genome sequencing in microfabricated high-density picolitre reactors:Margulies et al Nature (2005) doi:10.1038/ nature03959 N x 105 (100nt) reads per machine run Solexa/Illumina N x 107 (35nt) reads per machine run deep sequencing of Arabidopsis siRNA and miRNA

  19. sRNA loci -200kb window Becky Mosher and Frank Schwach

  20. PolIVb total loss PolIVb no loss 200 bp 200 bp 200 bp 200 bp 200 bp centromere telomere defining sRNA loci Define locus by maximum gap and minimum number of hits: Not a locus or part of a different locus More than 3 hits? -> accept as locus Arabidopsis flower expresses siRNAs match >4000 unique loci corresponding to >1 % of the genome Becky Mosher Frank Schwach

  21. wildtype nrpd1b nrpd1a 100 80 60 40 20 * * 0 locus 385 wildtype (19) nrpd1a (15) nrpd1b (13) many endogenous siRNAs direct DNA methylation IIIIIIIIIIIIIIIIII I I I I % CNN methylation Becky Mosher

  22. RNA directed epimutation in evolution?? novel RNA directed DNA methylation + transcriptional silencing of target locus maintenance of imprint through meiosis “heritable epimutation” natural selection expression of endogenous siRNA

  23. enhanced heritable variation due to epimutation * * Col-0 Col0 x Cvi Locus N Col0/Cvi* Locus N Col0/Cvi* Col0/Col0 Cvi*/Cvi* Cvi* epimutation would be subject to natural selection but may be unstable Susi Heimstädt

  24. production of P5CDH-specific siRNA in stress treated plants 100% RNA directed epimutation of and silencing of P5CDH giving constitutive salt stress tolerance Rare Selection of epimutants Etc etc targeted epimutation? Borsani, O., Zhu, J., Verslues, P.E., Sunkar, R., and Zhu, J.-K. (2005). Endogenous siRNAs derived from a pair of natural cis-Antisense Transcripts regulate salt tolerance in Arabidopsis. Cell 123, 1279-1291.

  25. http://www.princessleia.com/images/MyImages/essays/giraffe_lamark.jpghttp://www.princessleia.com/images/MyImages/essays/giraffe_lamark.jpg

  26. RNA silencing predates the evolutionary divergence of animals and plants Return to the RNAi world: rethinking gene expression and evolution CC Mello Nobel Lecture, December 8, 2006

  27. paramutation in mice Paul D. Soloway Paramutable possibilities Nature 441, 413-414 (25 May 2006) Rassoulzadegan, M., Grandjean, V., Gounon, P., Vincent, S., Gillot, I., and Cuzin, F. (2006). RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469-474

  28. implications of epigenetics • understanding of mechanisms that may be involved in generating heritable variation and that may contribute to descent with modification by means of natural selection • indications that heritable traits may be influenced by nurture

  29. learning to think with the left hand side of the brain

  30. learning to think with the left hand side of the brain

  31. learning to think with the left hand side of the brain

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