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Junk DNA

Junk DNA. Most human genome does not encode for proteins. Transposable elements in the human genome. Transposable elements. Barbara McClintock 1902-1992 Nobel Prize in Physiology or Medicine (1983). DNA transposons and retroelements. Retroelements. DNA transposons.

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Junk DNA

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  1. Junk DNA

  2. Most human genome does not encode for proteins

  3. Transposable elements in the human genome

  4. Transposable elements Barbara McClintock 1902-1992 Nobel Prize in Physiology or Medicine (1983)

  5. DNA transposons and retroelements Retroelements DNA transposons

  6. Transposable elements vs. genes in animal genomes Worm Fruit fly Oikopleura Fugu Chicken Mouse Human Genes 19.000 14.000 15.000 31.000 23.000 30.000 35.000 DNA transposons 3.000 400 100 8.000 13.000 112.000 294.000 Retroelements 600 1200 600 22.000 230.000 2.800.000 2.900.000

  7. Transposable elements can be lost without altering host fitness Rex3 C zebrafish sturgeon platyfish medaka killifish tilapia molly trout carp pike eel

  8. Orgel LE, Crick FH (1980) Selfish DNA: the ultimate parasite. Nature 284: 604-607.

  9. Transposable elements can negatively affect host genes

  10. Transposable elements can cause disease Element Organism Disease Gene Mechanism L1 Human Haemophilia A Factor VIII Insertion L1 Human DMD Dystrophin Insertion L1 Human Colon carcinoma APC Insertion Alu Human Breast cancer BRCA2 Insertion Alu Human Haemophilia B Factor IX Insertion Alu Human Dent's disease CLCN5 Insertion SVA Human Various Various Insertion L1 Mouse Myoclonus Glrb Insertion IAP Mouse Various Various Insertion L1 Human Glycogen storage dis.PHKBEctopic recombination (del) Alu Human Hunter disease IDS Ectopic recombination (del) Alu Human Wiskott-Aldrich sdr WASP Ectopic recombination (del) Alu Human Lesch-Nyhan sdr HPRT1 Ectopic recombination (del) Alu Human Lesch-Nyhan sdr HPRT Ectopic recombination (dupl) L1 Mouse Beige-like coat color Lystbg Ectopic recombination (del) Alu Human Ornithine AT def. OAT Exonisation Alu Human Sly syndrome GUSB Exonisation Alu Human Alport syndrome COL4A3 Exonisation

  11. Anticancer mutagenic insertion in the platyfish Xmrk Txi-1

  12. Proposed and demonstrated functions of transposable elements Gene regulation X chromosome inactivation Telomere maintenance (Drosophila) Gene and genome evolution / Genetic diversity …

  13. Transposable elements are drivers of gene evolution About 4% of human genes contain sequences derived fromtransposable elements in their coding region (Nekrutenko and Li 2003) About 25% of human promoter regions containsequences derivedfrom transposable elements (Jordan et al. 2003)

  14. Comparative genomics of transposable elements in vertebrates

  15. Comparative genomics of transposable elements in vertebrates

  16. Transposable elements

  17. Transposable elements in the human genome

  18. Many transposable elements have been lost from the mammalian lineage

  19. Human 3 clades - - 3 clades Retrotransposon diversity in the fish lineage Zebrafish Fugu Tetraodon Non-LTR retrotransposons LTR retrotransposons Penelope-like Total 7 clades 15 clades 1 clade 23 clades 6 clades 15 clades 2 clades 23 clades 6 clades 8 clades 2 clades 16 clades

  20. Ty3/Gypsy retrotransposons

  21. Diversity of Gypsy/Ty3 LTR retrotransposons in fish genomes Barthez Osvaldo Gypsy Fly Ciona Fly Sea urchin Gmr1 Atlantic cod Nematode Maggy Fungus Sushi Gmr1L Ty3 Yeast Ciona Trematode Rex8 Fly CsRn1 silkworm Ciona Jule Ciona nematode sea urchin SURL 0.1 changes SURL-like

  22. Homo sapiens 0 0 0 0 0 fossils 0 0 0 0 0 (fossils) Gypsy/Ty3 retrotransposons in the vertebrate lineage Pufferfish Takifugu rubripes Pufferfish Tetraodon nigroviridis Zebrafish Danio rerio Clades SURL SURL-like Jule CsRn1 Sushi Barthez Gmr1(-like) Rex8 Osvaldo Total 8 20 10 10 140 290 25 55 10 0 560 5 fossils fossils 8 25 120 45 15 fossils 0 213 9 20 20 10 8 700 85 510 12 25 1390 0: not detected

  23. Sequences related to gag of Sushi in mammalian genomes

  24. Sushi-ichi retrotransposons from fish Pro RT/RNaseH Int LTR LTR pol gag CCHC Poulter et al. 1998

  25. Sushi-ichi pufferfish Pro RT/RNaseH Int LTR LTR 1 kb pol gag CCHC Mart1 Human Mouse 3’ UTR 5’ UTR Human Mart2 Mouse Human Mart3 Mouse Human Introns Mart4 Mouse Human Mart5 Mouse Human Mart6 Mouse Human Mart7 Mouse Human (A-C) Mart8 (x3) The Mart gene family Mouse (1-2A/B) 1.5 kb Human Mart9 Mouse

  26. Southern blot analysis of mouse Mart genes

  27. RT/RNaseH Int Chr Pro Sushi Pol Gag CCHC Mart1 The Mart family Mart2 Mart3 Mart4 Mart5 Mart6 200 aa Mart7 Mart8 Mart9

  28. Mart genes evolve under purifying (negative) selection GeneKAKSKA/KS Mart10.18 0.55 0.33 Mart2 0.13 0.65 0.20 Mart30.22 0.45 0.49 Mart40.23 0.47 0.49 Mart50.06 0.46 0.13 Mart6 0.03 1.0 0.03 Mart70.18 0.43 0.42 Mart80.21 0.59 0.36 Mart9 0.06 0.20 0.30 Comparisons mouse/human

  29. (Molecular) domestication “domesticated” “wild”

  30. Why are transposable element proteins interesting for the host? TE proteins can - bind nucleic acids - copy nucleic acids - break nucleic acids - join nucleic acids - degrade nucleic acids - process proteins - interact with proteins - …

  31. Sushi-like (Gag) Mart7 Zf Frog Human Chimpanzee Fugu Salamander Gorilla Mart8s Mouse Dog Cow Frog Rat Macaque Fugu Human A-C Chimpanzee Trout Dog-1-4 Cow Pig Mouse-1 100 Dog Mart9 Mouse-2a/b Rat Mouse Rat 87 Opossum 100 Human 100 Human Chimpanzee Chimpanzee Mart2 Baboon Marmoset 96 Cow Cow Pig Bat 100 Zf Sheep Dog Cat Shrew 83 69 Galago 100 Mouse Rat Chimpanzee Human Human Chimpanzee Dog Orangutan Dog Mart1 100 Mart6 100 Mouse Rat 100 Rat Human Macaque Mouse Chimpanzee Rat Dog Mouse Mouse Rat Mart5 Chimpanzee Dog Human Dog Chimpanzee Mart3 Mouse Rat Human Zf Zf Mart4

  32. Evolution of Mart genes and Sushi retrotransposons in the vertebrate lineage Mart Mart Duplication(s)? Domestication(s) Retrotransposon loss Mart Marsupials vs. placental mammals 170 myr Mart Mammals vs. birds 310 myr Mart Loss? Amniotes vs. amphibians 360 myr - Tetrapods vs. ray-finned fish 450 myr Sushi-like Sushi-like

  33. Possible evolutionary scenarios leading to molecular domestication

  34. autosomal imprinted autosomal autosomal imprinted Sushi-like (Gag) X Mart7 Frog Human Chimpanzee Fugu Mart8s Salamander Gorilla Mouse Dog Cow Frog Rat Macaque X X X Fugu Human A-C Chimpanzee Trout Mart9 Dog-1-4 Cow Pig Mouse-1 100 Dog X Mouse-2a/b Rat Mouse Rat 87 Opossum 100 Human Mart2 100 Human Chimpanzee Chimpanzee Baboon Marmoset 96 Cow Cow Pig Bat 100 Sheep Dog Cat Shrew 83 69 Galago 100 Mouse Rat Chimpanzee Human Human Chimpanzee Dog Mart6 Orangutan Dog Mart1 100 100 Mouse Rat 100 Rat Human Macaque Mouse Chimpanzee Rat Dog Mouse Mouse Rat X Mart5 Chimpanzee Dog Human Dog Mart3 Chimpanzee Mouse Rat Human X X Mart4

  35. Two autosomal Mart genes, PEG10 (Mart2) and PEG11/Rtl1 (Mart1) are subject to parental imprinting and paternally expressed. Imprinting of both genes is controlled by differentially methylated regions. Two miRNA genes are located in Rtl1, are transcribed in an antisense orientation to Rtl1 and expressed exclusively from the maternal chromosome (reciprocal imprinting). RNA interference. Since RNA interference and methylation are considered as defence mechanism against mobile DNA, genome imprinting of gag-related genes might be related to retrotransposon silencing.

  36. Expression of Mart genes in mouse adult tissues

  37. Expression of Mart genes during mouse embryogenesis E14.5, RT-PCR

  38. Function(s) of Mart proteins in mammals? Immunity against retrotransposons Transcription factors Control of cell proliferation and apoptosis Cell adhesion and migration

  39. Paper function mart

  40. Other Gypsy/Ty3gag-derived genes in the human genome Campillos et al. 2006

  41. Another family of gag-derived neogenes in mammals

  42. The Ma family of gag-derived neogenes in mammals Wills et al. 2006

  43. The Ma family of gag-derived neogenes in mammals Hsa14 Hsa14 Hsa8 HsaX HsaX Paper Ma HsaX Wills et al. 2006

  44. Function(s) of Ma proteins in mammals Apoptosis (Ma4) ????

  45. SCAN transcription factors 59 and 40 genes in human and mouse, respectively Regulation of core body temperature, feeding behaviour and obesity(PW1/Peg3) Control of lipid metabolism (ZNF202) Regulation of hippocampal neuronal cholesterol biosynthesis (NRIF) Muscle stem cell behaviour and muscle atrophy (PW1/Peg3) Regulation of pluripotency of embryonic stem cells (ZNF206) Hematopoiesis (MZF1) Negative regulator of the hypoxia-inducible factor-1alpha (ZnF197) Roles in apoptosis, cell proliferation (several genes) Subject to parental imprinting: Peg3/Pw1 (paternally expressed)

  46. Interactome ofGag-derived proteins in mammals Campillos et al. 2006

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