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Curso de postgrado GENOMICA, PROTEOMICA Y BIOINFORMATICA

Curso de postgrado GENOMICA, PROTEOMICA Y BIOINFORMATICA DESARROLLO DE ESTRATEGIAS TERAPEUTICAS PARA EL NUEVO MILENIO Enero 2005. Genómica: Genómica comparada/ evolución del genoma. Dr. Jordi Garcia Fernàndez Departament de Genètica Facultat de Biologia Universitat de Barcelona

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Curso de postgrado GENOMICA, PROTEOMICA Y BIOINFORMATICA

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  1. Curso de postgrado GENOMICA, PROTEOMICA Y BIOINFORMATICA DESARROLLO DE ESTRATEGIAS TERAPEUTICAS PARA EL NUEVO MILENIO Enero 2005 Genómica: Genómica comparada/ evolución del genoma Dr. Jordi Garcia Fernàndez Departament de Genètica Facultat de Biologia Universitat de Barcelona e.mail: jordigarcia@ub.edu

  2. La paradoxa del valor C, o no es una paradoxa?

  3. Las grandes transiciones del Reino Animal Poríferos Diblásticos Cnidarios Acelomados Pseudocelomados Protostomados Celomados TriblásticosBilaterales Multi-celularidad Simetría bilateral Deuterostomados Celoma

  4. Las grandes transiciones del Reino Animal Vertebrados Poríferos Diblásticos Cnidarios Acelomados Pseudocelomados Protostomados Celomados TriblásticosBilaterales Multi-celularidad Simetría bilateral Celoma Cresta neural, vértebras

  5. Las grandes transiciones del Reino Animal Vertebrados Simetría bilateral Celoma Poríferos Diblásticos Cnidarios Acelomados Pseudocelomados TriblásticosBilaterales Protostomados Celomados Multi-celularidad Cresta neural, vértebras

  6. Las grandes transiciones del Reino Animal Acelomados Pseudocelomados Vertebrados Simetría Bilateral y celoma Poríferos Diblásticos Cnidarios TriblásticosBilaterales Protostomados Celomados Multi-celularidad Cresta neural, vértebras

  7. Las grandes transiciones del Reino Animal Acelomorfos Vertebrados Simetría bilateral Celoma Simetría Bilateral y celoma Poríferos Diblásticos Cnidarios TriblásticosBilaterales Protostomados Multi-celularidad Cresta neural, vértebras Ruiz-Trillo y col, 1999, 2002 Jondelius y col., 2002 Telford y col., 2003 Pasquinelli y col., 2003

  8. Cambrian Explosion Origin of Bilaterians Origin of Vertebrates Origin of Metazoan Protostomes Deuterostomes Evolutionary Transitions in Metazoans

  9. Ohno, S. (1970) “Evolution by Gene Duplication” Propuso que genes extra (duplicados) son material potencial para incrementar la complejidad Why? Susumu Ohno 1928-2000

  10. Ohno, S. (1970) “Evolution by Gene Duplication” Propuso que genes extra (duplicados) son material potencial para incrementar la complejidad Why? “Only the cistron (gene) which became redundant was able to escape from the relentless pressure of natural selection, and by escaping, it accumulated formerly forbidden mutations to emerge as a new gene locus” Lo que hoy denominamos NEOFUNCIONALIZACION Susumu Ohno 1928-2000

  11. Ohno, S. (1970) “Evolution by Gene Duplication” Propuso que genes extra (duplicados) son material potencial para incrementar la complejidad Why? “natural selection merely modified, while redundancy created” Susumu Ohno 1928-2000

  12. NEW FUNCTION A A A A B Innovation A A B A A A C Innovation + redundancy A A A s A p Inactivation (pseudogene) EVOLUTION BY GENE/GENOME DUPLICATION

  13. Mecanismes de duplicació génica Recombinació no homòloga No disjunció meiòtica

  14. El (los) complejo(s) Hox

  15. Duplicació: innovació i redundància

  16. L’origen dels vertebrats: invencions evolutives

  17. Vertebrados Cordados La posición privilegiada de anfioxo amniotes ray-finned fishes cyclostomes cephalochordates tunicates

  18. Phylum Chordata; Subphylum Cephalochordata ANFIOXO, LANCETA, CEFALOCORDADOS • Género Branchiostoma, 28 especies • Género Epigonichthys, 1 especie • Ampliamente distribuidos en mares templados y tropicales • Adultos en hábitats arenosos • Profundidad 0,5-40? m • Reproducción sexual • Sexos separados • Tampa (Florida, USA) • Quindao (China) • Banyuls (Francia)

  19. Homeobox gene duplication (1994) 10 years later…. Garcia-Fernàndez & Holland, Nature 1994, Holland et al. Development 1994

  20. Although the analyses are sensitive to the imperfect quality of the gene predictions, our results so far are insuficient to settle whether two rounds of WGD occurred around 500 Myr ago. It may be possible to resolve the issue by systematically estimating the time of each of the many gene duplication events on the basis of sequence divergence, although this is beyond the scope of this report. Another approach to determining whether a widespread duplication occurred at a particular time in vertebrate evolution would be to sequence the genomes of organisms whose lineages diverged from vertebrates at appropriate times, such as amphioxus.

  21. Grups de paralogia, sintènia conservada

  22. 3. Explosió Cámbrica 2. Origen dels Bilateris 2R 1. Origen dels metazous

  23. 2R a l‘origen dels vertebrats, R en els peixos teleostis

  24. De qui son quins gens? Comparant l’home i el ratolí Dec 2002 2001

  25. 2000 2001 2002

  26. Ratolí / home 2002 Peix / home 2004

  27. Els genomes humà i murí: bricolatge cromosòmic NCBI 2003

  28. Paralogia dins de paralogia, i mes sintènia…?

  29. El (los) complejo(s) Hox

  30. Origen y evolución de los complejos Hox y ParaHox UrProtoHox-like UrProtoHox gene Evx/Mox ancestor Ancestral Hox-like cluster (ProtoHox cluster + Evx/Mox ancestor ) Hox-like cluster segmental TANDEM duplication Primordial ParaHox cluster + Mox Primordial Hox cluster + Evx Coupled Hox-like cluster BREAKAGE ParaHox A Hox A ParaHox B Hox B Primordial ParaHox cluster Primordial extended Hox cluster (Mox + Primordial Hox + Evx) Hox C ParaHox C ParaHox D Hox D ParaHox cluster (origin of vertebrates) Extended Hox cluster (origin of vertebrates) Vertebrate duplications Vertebrate duplications Coupled Hox-like cluster

  31. Hox y Eubilateria (transicions) Celoma Bilateralitat AP/DV eMS aNS BG EX D L E Acoelomorpha CNIDARIA Baguñà, 2002

  32. Hox y Eubilateria (hipòtesi) Expansió Hox central 1 3 AP/DV eMS aNS BG EX PG3 Central Posterior Anterior 1/2 9/13 Evx Xlox Gsh Cdx Mox 1 2 3 4 5 6/8 9/13 Evx Gsh 3 Cdx Mox Anterior PG3 Central Post E/M PG3 Central Posterior Anterior 1/2 9/13 Evx Gsh Cdx Mox + 2 HOX + 1 ParaHox D L E Acoelomorpha 2 Hox (A+P) 2 ParaHox (A+P) CNIDARIA Garcia-Fernàndez, Hereddity (en prensa)

  33. Transicions AP/DV eMS aNS BG EX PORIFERA ProtoHox? D L Multicelularitat E Acoela Simetría CNIDARIA

  34. Perspectives AP/DV eMS aNS BG EX CHOANOFLAGELLATA D L Multicelularidad E Acoela Simetría CNIDARIA PORIFERA

  35. Comunicación celular combinatoria de dominios King & Carroll, 2001 King et al., 2003

  36. Grandes transiciones del Reino Animal AP/DV eMS aNS BG EX Vertebrados D L Multicelularidad E Bilateria Acoela Simetría CNIDARIA PORIFERA Eubilateria CHOANOFLAGELLATA

  37. Grandes transiciones del Reino Animal AP/DV eMS aNS BG EX L E Nemertodermatida Acoela CNIDARIA PORIFERA CHOANOFLAGELLATA Vertebrados D Multicelularidad Bilateria Simetría Eubilateria

  38. Cys cluster - Leu rich motif - Cys cluster - IgG -C2 TK Caracterización Estructural de AmphiTrk N-terminal extension IgG -C2 Cys - cluster Cys - cluster Ror - like Leu - rich motif Leu - rich motif Cys domains Cys - cluster IgGV Cys - cluster Kringle IgG -C2 IgG -C2 domain Extracelular Intracelular TK TK TK TK TrkA AmphiTrk TrkB Ltrk Dror / Dnrk Dofftrk TrkC Kesteren et al, 1999

  39. Domain shuffling, exon shuffling? TrkA/TrkB/TrkC 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 2 3 4 5 6-7 8 9-10 11-12 13-14 15 16 17 AmphiTrk IgG-C2 domain 1 IgG-C2 domain 2 Tyrosine Kinase domain Transmembrane domain Cysteine Cluster Leucine Rich Region Shc/SNT tansduction domain 9 “Promiscuity” mini-exon

  40. Modulos/Kits/Redes/GRN

  41. Notch signaling Exocrine Transcription Intestinal Transcription Suc/Isom. IFABP Amylase Jagged1 Jagged2 Dll1 Gut ? Gut Gut MIST1 Wnt/b-cat. Cdx1 GATA4 ? Notch1 Notch2 Cdx2 Gut ? Ptf1a Hes1 nr5a2 ? Core Endodermal program Pancreas Determination Endocrine fate Allocation Endoderm Establishment GATA6 Oct4 HNF1a HNF4 HlxB9 ? Sox9 ? Via Sox17 or Mix? Six3 ENDODERM SMAD2/SMAD4 /SMAD4 FoxA2 PDX1MED Ngn3-E2A Eye Via nkx2.2? X.L Nkx2.2 Activin or nrf Cell cycle Exit HNF1b HNF6 X.L Eye Sox17 NeuroD-E2A Prox1 FGF10 Indirectly Z.F Eye Nkx6.1 Z.F Eye COUP-TFII Mixer/Bon Casanova Hex Z.F Pax6 Pax4 Pax2 C/EBP-a Nodal Gut Pbx1 HNF1a Pax4 Pancreas FoxA2 Insulin PDX1HIGH FoxA3 Glucagon Brn4 Eye Gli2 SMAD1/SMAD4 /SMAD4/ Isl1 FoxO1 HNF4 LIVER TRANSCRIPTION FoxA1 BMP Also involving most members of the core endodermal program mafA < =? > L-Maf Shh Beta-cell Transcription Alpha-cell Transcription Symbols How to use this file: 1. Download file to disk. 2. Open File by double clicking. Select “slideshow” option in PowerPoint (PC: press F5). Within the slideshow, point-and-click on arrow, gene, or symbol for exiting to hyperlinked information. Hyperlink information will display when hovering over symbol. Clicking within non-linked areas will terminate the slideshow. Press F5 to resume slideshow. For best results, a 17’’ screen, or larger, is recommended. Documented interaction, positive Hyperlink, review on subject Documented interaction, negative Link demonstrated in Zebrafish Z.F Documented interaction, not in pancreas Link demonstrated in Xenopus Laevis X.L Autoregulation Hyperlink, description of targeted mutation of gene Suggested interaction, not proven Extra-cellular signaling Comment on auto-regulation arrows: Green: The gene acts by a self-sustainable mechanism – intrinsic stability of network Red: The gene may act by a threshold mechanism – intrinsic instability of network Comment on targeted mutation links: Studies of the genes by targeting mutations may have been performed by several independent groups, and several publications may exist regarding a particular gene. Furthermore, independent targeting may have been performed, as is the case for e.g. Pdx1, HB9, Ptf1a, NeuroD. Here, each link branches out only to one given study. Please consult the text for additional information to other references having provided information about the role of the gene in pancreatic development using a targeted mutation approach. Regulatory interactions during pancreatic development, by Jan Jensen. Barbara Davis Center for Childhood Diabetes, U. Colorado Health Sciences Center.

  42. Niveles de complejidad en la evolución génica y genómica Antonio García-Bellido 1.- Invención de dominios proteicos 2.- Ensamblaje de dominios proteicos -exon shuffling -duplicación intragénica 3.- Creación de redes génicas 4.- Redes génicas complejas -duplicación de redes -conexiones entre redes Duplicación génica /Regulació génica (co-opció)

  43. Genòmica comparada • conservació de grans regions genòmiques en diferents organismes (conservació de la sintènia) • evolució del genoma/bricolatge genòmic • duplicacions i poliploiditzacions • Complexitat del genoma/complexitat de l’organisme • Inferències a partir de sintènia • Sintènia del genoma ancestral • Reordenaments desprès de la duplicació • %Perdua/Divergència gènica Evidència de duplicacions genòmiques -Saccharomyces cerevisae -origen dels vertebrats -Llinatges particulars -Xenopus -Teleòstis -Planàries -Llinatges de plantes

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