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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 30.000 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. Only ?

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

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

  14. 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)

  15. Comparative genomics of transposable elements in vertebrates

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

  17. Ty3/Gypsy retrotransposons

  18. 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

  19. 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

  20. Sequences related to gag of Sushi in mammalian genomes

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

  22. ? gag

  23. 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

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

  25. 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

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

  27. 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 - …

  28. 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

  29. 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

  30. 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.

  31. Expression of Mart genes in mouse adult tissues

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

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

  34. Paper function mart

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

  36. The Ma family of gag-derived neogenes in mammals Hsa14 Hsa8 HsaX Hsa14 HsaX HsaX Functions: Apoptosis (Ma4), ??? Wills et al. 2006

  37. 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)

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

  39. Gypsy/Ty3 LTR retrotransposons Pro RT/RNaseH Int LTR LTR pol gag CCHC

  40. Domesticated integrase gene: GIN-1 Mammals, birds and reptiles On the Z chromosome in birds - Conserved HHCC motif - Conserved DDE motif * *

  41. Domesticated integrase gene: MGC80999 Birds, reptiles, amphibians and fish - Conserved HHCC motif - Non-conserved DDE motif

  42. Ancient domestication of an integrase gene in vertebrates MGC 80999 Fish Amphibians Duplication event Reptiles Birds Mammals Molecular domestication event Fish Amphibians Reptiles Birds Mammals GIN-1

  43. Domestication/fusion of a retrovirus integrase domain in mammals KIAA1305 NFATC4 KIAA1305 CBLN3 KIAA0323 N-ter C-ter Similar to C-terminus of KIAA0323 Retrovirus integrase- derived domain

  44. Domesticated transposable element genes in human genome

  45. Putative and confirmed examples of protein-coding neogenes derived from TEs P Gene (family) Protein properties and functions Ancestral gene Ancestral TE Organisms Rag1 nuclease, V(D)J recombination, adaptive immune system transposase Transib DNA transposon vertebrates Daysleeper DNA binding protein, gene regulation, plant development transposase hAT DNA transposon Arabidopsis Gary unknown transposase hAT DNA transposon cereal grasses Tram unknown transposase hAT DNA transposon mammals Zbed4 unknown transposase hAT DNA transposon mammals KIAA0543 unknown transposase hAT DNA transposon mammals P52rIPK binding to inhibitor of interferon-induced protein kinase PKR transposase hAT DNA transposon mammals Buster1-3 unknown transposase hAT DNA transposon mammals Dref transcription factor, regulation of DNA replication transposase hAT DNA transposon Drosophila Lin-15B regulator of vulval developmenttransposase hAT DNA transposon Caenorhabditis Cenp-b DNA binding protein, centromere function transposase Pogo DNA transposon eukaryotes Pdc2/Rag3 transcription factor, regulation of pyruvate utilization transposase Pogo DNA transposon yeast Jerky neuron mRNA-binding protein, mutated in epilepsy syndromes transposase Tigger/pogo DNA transposon mammals Jerky-like unknown transposase Tigger/pogo DNA transposon mammals KIAA0461 unknown transposase Tigger/pogo DNA transposon mammals Tigger-derived unknown transposase Tigger/pogo DNA transposon mammals Metnase DNA integration, radiation resistance, DNA break repair transposase Mariner DNA transposon human P-derived DNA binding protein transposase P DNA transposon Drosophila Phsa/Pgga unknown transposase P DNA transposon mammals, birds PiggyMac Elimination of germ-line sequences from macronucleus transposase PiggyBac DNA transposon Paramecium Pgbd1-4 unknown transposase PiggyBac DNA transposon human Pgbd5 unknown transposase PiggyBac DNA transposon bony vertebrates HarbI1 unknown transposase Harbinger DNA transposon bony vertebrates Fhy3, Far1 transcription factors, sensitivity to far-red light transposase Mutator DNA transposon Arabidopsis Mustang unknowntransposase Mutator DNA transposon flowering plants Gin-1 unknown integrase Ty3/gypsy LTR retrotransposon mammals c-integrase unknown integrase/tpase Maverick transposon mammals Fob1p replication terminator protein, rDNA metabolism integrase/tpase Maverick/LTR element? baker's yeast Telomerase ribonucleoprotein, reverse transcriptase, telomere replication RT retroelement eukaryotes Peg10/Mart2 cell proliferation, transcription factor?, placenta formation gag Ty3/gypsy LTR retrotransposon mammals Ldoc1/Mart7 inhibition of NF-kappaB activation, induction of apoptosis gag Ty3/gypsy LTR retrotransposon mammals Other Mart’s unknown gag Ty3/gypsy LTR retrotransposon mammals Map-1/Ma1 Bax-associating protein, induction of apoptosis gag LTR retrotransposon/retrovirus mammals Other Ma genes neuronal autoantigens in paraneoplastic neurological diseases gag LTR retrotransposon/retrovirus mammals Fv1 murine leukemia virus restrictiongag vertebrate retrovirus mouse Syncytin-1 membrane glycoprotein, cell fusion, placenta formation envelope vertebrate retrovirus human Syncytin-2 membrane glycoprotein, cell fusion, placenta formation envelope vertebrate retrovirus human Syncytin-A/B membrane glycoprotein, cell fusion, placenta formation envelope vertebrate retrovirus mouse Other env’s unknown envelope vertebrate retrovirus mammals Iris defence against viruses? envelope Kanga BEL-like retrovirus Drosophila Iris-like defence against viruses? envelope Kanga BEL-like retrovirus mosquito

  46. Best-studied examples of protein-coding neogenes derived from TEs P Gene Protein properties and functions Ancestral TE Organisms Transposase-derived genes Rag1 nuclease, V(D)J recombination, adaptive immune system Transib DNA transposon vertebrates Daysleeper DNA binding protein, gene regulation, plant development hAT DNA transposon Arabidopsis Cenp-b DNA binding protein, centromere, transposon restriction Pogo DNA transposon eukaryotes PiggyMac Elimination of germ-line sequences from macronucleus PiggyBac transposon Paramecium Reverse transcriptase-derived genes (?) Telomerase ribonucleoprotein, RT, telomere replication Retroelement eukaryotes Gag-derived genes Fv1 murine leukemia virus restriction vertebrate retrovirus mouse Envelope-derived genes Syncytin-1 membrane glycoprotein, cell fusion, placenta formation vertebrate retrovirus human Syncytin-2 membrane glycoprotein, cell fusion, placenta formation vertebrate retrovirus human Syncytin-A/B membrane glycoprotein, cell fusion, placenta formation vertebrate retrovirus mouse Iris defence against viruses? Kanga BEL-like retrovirus Drosophila

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