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CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS EVOLUTION in immunity Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 EVOLUTION OF THE IMMUNE SYSTEM 716 Genomes and evolution since the Echinoderms Sea Tubulins urchin verte Hagfish Cartilaginous Zebrafish, A PufferfIsh Mammals Mouse Reptiles Birds Chick 600 400 I ( 200 0 MIllIon years ago C 1996 Current Oplnton I” Genetics & Development relationships phyla. (The exact branching among extant deuterostome order of lampreys classes and hagfish the last round of homogenization impossible fish Shark I of the second before Amphioxus I and actins-representatives Lamprey, Cephalochordates L gene. lawless fish Tunicate I------ target of terminal target gene-are encoded by multiple because they need to be expressed at high leve undergo periodic homogenization by gene conversi cycles of duplication and loss. Homogenization paralogs, by whichever mechanism, erases their mo evolutionary record which renders inference of any Urochordates Sunday, 14 June 2009 of all jawed Innate immunity Toll like Receptor (TLR) of terminal Phylogenetic ancestor (reviewed in [18]). The historical record of genomeevents that is retained in fundamental regulators b of stringent selective constraints is thus erased in th Protostomes 800 last common CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fiaure 1 and is a matter third class of terminal target gene comprises ubiquitously expressed, single-copy housekeeping such as manganese superoxide dismutase and the subunits of RNA polymerases. As these genes a required in several copies to maintain a high expression level, they have survived genome duplic merely as single copy genes. In this class of terminal gene, records of past duplications are thus also lost Finally, the fourth class of terminal target g exemplified by the olfactory receptor and immunoglob gene families. These proteins interact with liga environmental origin and potentially unlimited di Structural alterations in the absence of regulatory c allow new duplicates to interact with novel ligands. duplicated Technical paralogsUniversity that ofinteract Denmark with - DTU new ligand positively selected, which has caused o Department of systems biology expansion gene families since the origin of vertebrates and their records of early genome-wide events. Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS TOLL LIKE RECEPTORS TLRs share a prototypical organization of N-terminal (N) extracellular leucine-rich repeat (LRR) motifs. TLRs are dimerized and the ectodomain forms a horseshoeshaped solenoid. François Leulier & Bruno Lemaitre Nature Reviews Genetics 9, 165-178 (March 2008) Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS TOLL LIKE RECEPTORS CAN RECOGNIZE PATTERNS EVOLUTION OF THE IMMUNE SYSTEM 716 Genomes and evolution since the last common ancestor of all jawed (reviewed in [18]). The historical record of genomeevents that is retained in fundamental regulators b of stringent selective constraints is thus erased in th Protostomes of terminal target gene. Echinoderms Sea Tubulins urchin Lamprey, before Cephalochordates Amphioxus Hagfish Cartilaginous fish Zebrafish, PufferfIsh Mammals Mouse Reptiles Birds Chick I I 600 400 I ( 200 0 MIllIon years ago C 1996 Current Oplnton I” Genetics & Development Phylogenetic Sunday, 14 June 2009 relationships phyla. (The exact branching among extant deuterostome order of lampreys the last round of homogenization third class immune of terminal system target gene Adaptive A Shark L of the second lawless fish Tunicate I------ and actins-representatives of terminal target gene-are encoded by multiple because they need to be expressed at high leve undergo periodic homogenization by gene conversi cycles of duplication and loss. Homogenization paralogs, by whichever mechanism, erases their mo evolutionary record which renders inference of any Urochordates 800 verte CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fiaure 1 classes and hagfish and is a matter impossible comprises ubiquitously expressed, single-copy housekeeping such as manganese superoxide dismutase and the subunits of RNA polymerases. As these genes a required in several copies to maintain a high expression level, they have survived genome duplic merely as single copy genes. In this class of terminal gene, records of past duplications are thus also lost Immunoglobulins (Abs and TCRs) Finally, the fourth class of terminal target g exemplified by the olfactory receptor and immunoglob gene families. These proteins interact with liga environmental origin and potentially unlimited di Structural alterations in the absence of regulatory c allow new duplicates to interact with novel ligands. duplicated Technical paralogsUniversity that ofinteract Denmark with - DTU new ligand positively selected, which has caused o Department of systems biology expansion gene families since the origin of vertebrates and their records of early genome-wide events. EVOLUTION OF THE IMMUNE SYSTEM 716 Genomes and evolution since the last common ancestor of all jawed (reviewed in [18]). The historical record of genomeevents that is retained in fundamental regulators b of stringent selective constraints is thus erased in th Protostomes of terminal target gene. Echinoderms Sea Tubulins urchin Lamprey, before Cephalochordates Amphioxus No Immunoglobulins the last round of homogenization Hagfish Cartilaginous Zebrafish, A PufferfIsh Mammals Mouse Reptiles Birds Chick I I 600 400 I ( 200 0 MIllIon years ago C 1996 Current Oplnton I” Genetics & Development Phylogenetic Sunday, 14 June 2009 relationships phyla. (The exact branching among extant deuterostome order of lampreys classes and hagfish impossible fish Shark L of the second lawless fish Tunicate I------ and actins-representatives of terminal target gene-are encoded by multiple because they need to be expressed at high leve undergo periodic homogenization by gene conversi cycles of duplication and loss. Homogenization paralogs, by whichever mechanism, erases their mo evolutionary record which renders inference of any Urochordates 800 verte CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fiaure 1 and is a matter third class of terminal target gene comprises ubiquitously expressed, single-copy housekeeping such as manganese superoxide dismutase and the subunits of RNA polymerases. As these genes a required in several copies to maintain a high expression level, they have survived genome duplic merely as single copy genes. In this class of terminal gene, records of past duplications are thus also lost Finally, the fourth class of terminal target g exemplified by the olfactory receptor and immunoglob gene families. These proteins interact with liga environmental origin and potentially unlimited di Structural alterations in the absence of regulatory c allow new duplicates to interact with novel ligands. duplicated Technical paralogsUniversity that ofinteract Denmark with - DTU new ligand positively selected, which has caused o Department of systems biology expansion gene families since the origin of vertebrates and their records of early genome-wide events. Hagfish Lamprey Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS ADAPTIVE IMMUNITY? •Capacity •The of transplantation rejection responses to skin allografts is specific •Accelerated second-set rejections indicates immunological memory. Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS ADAPTIVE IMMUNITY •Able to produce serum antibodies. •Responses have been connected with cells that are morphologically similar to the lymphocytes from jawed vertebrates Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS CHALLENGE WITH BACTERIA Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey Zeev Pancer1,2, Chris T. Amemiya6, Götz R. A. Ehrhardt1,5, Jill Ceitlin7, G. Larry Gartland1,4 & Max D. Cooper1,2,3,4,5 1 Division of Developmental and Clinical Immunology, Departments of 2Medicine, 3Pediatrics and 4Microbiology, and the 5Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA 6 Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, 98101, USA 7 University of Michigan, Ann Arbor, Michigan 48109, USA ........................................................................................................................................................................................................................... Although jawless vertebrates are apparently capable of adaptive immune responses, they have not been found to possess the recombinatorial antigen receptors shared by all jawed vertebrates. Our search for the phylogenetic roots of adaptive immunity in the lamprey has instead identified a new type of variable lymphocyte receptors (VLRs) composed of highly diverse leucine-rich repeats (LRR) sandwiched between amino- and carboxy-terminal LRRs. An invariant stalk region tethers theof VLRs the cell Technical University Denmarkto - DTU of systems biology for an surface by means of a glycosyl-phosphatidyl-inositol anchor. To generate rearranged VLR genes of Department the diversity necessary anticipatory immune system, the single lamprey VLR locus contains a large bank of diverse LRR cassettes, available for insertion Sunday, 14 June 2009 an incomplete germline VLR gene. Individual lymphocytes express a uniquely rearranged VLR gene in monoallelic fashion. into CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS articles Nature 430, 174-180 (8 July 2004) © 20 8. Alder, M.N. et al. Nat. Immunol. 9, 319–327 (2008). 10. Gai, S.A. & Wittrup, K.D. Curr. Opin. Struct. Biol. 17, 467–473 (2007). amenable to molecular engineering, and the presence of usually two or three hypervariNEWS AND VIEWS able solvent-exposed sites per module should facilitate targeting of these residues by random mutagenesis in vitro to increase affinity Lamprey VLR genefor Mammalian antibody genes or alter specificity, as previously shown Heavy chain Light chain engineered synthetic LRR proteins1. Finally, Preassembly VLRs LRR in lamprey lymphocytes are assembled LRR LRR LRRIan MacLachlan LRR SP Stalk V V V J J J C V V V D D J J J C germline NT NT CT CT CT by a process of gene conversion through genes homologous regions that can span just a few Leukocyte-directed, small interfering (si)RNA against cyclin D1 shows nucleotides. To increase the combinatorial Assembly promise for treatment of inflammatory bowel disease. RAG-mediated diversity of a VLR library, it might there- from flanking rearrangement LRR cassettes foreCbeC possible to recapitulate this process C C C C C C by shuffling domains through homologous Colitis and Crohn’s diseaseMature are debilitating of treatment—can bring about long-term C C C C CCCC LRR inflammatory recombination in vivo using yeast surface they are encumbered bowel diseases in which the remission, SP LRR Stalk GPI Hydrophobic CP V J C V D J by C dose-limlymphocyte CT NT genes causing iting side effects. A recent paper by Shimaoka display10. The most ancient antigen receptors digestive tract becomes inflamed, may soon take a central place in the biotech- severe diarrhea and abdominal pain that and colleagues1 in Science describes a more can lead to life-threatening complications. targeted approach in which siRNA against nology arena. Although anti-inflammatory and immu- cyclin D1 (CyD1) is directed to leukocytes 1. Binz, H.K., Amstutz, P. & Plückthun, A. Nat. Cell-bound nosuppressive drugs—the two main classes expressing β7 integrin. Biotechnol. 23, 1257–1268 (2005). antigen receptors N EWS A Nature N D430,V 174–180 I E W(2004). S 2. Pancer, Z. et al. CyD1, a cell cycle regulator, is upregulated 3. Herrin, B.R. et al. Proc. Natl. Acad. Sci. USA 105, locally, in association with inflammatory 2040–2045 (2008). bowel disease, in both epithelial and immune Ian MacLachlan is at Protiva Biotherapeutics 4. Kim, H.M. et al. J. Biol. Chem. 282, 6726–6732 1 show that (2007). cells. Shimaoka and colleagues Inc., 100-3480 Gilmore Way, Burnaby, BC, Humoral 5. Pancer, Z. & Cooper, M.D. Annu. Rev. Immunol. 24, Canada, V5G 4Y1. leukocyte-directed CyD1 siRNA inhibits the antibodies 497–518 (2006). e-mail: [email protected] intestinal inflammatory response in a mouse 6. Alder, M.N. et al. Science 310, 1970–1973 (2005). LRR V LRR V LRR V LRR V LRR V LRR V LRR V LRR V LRR V LRR V LRR 1 LRR V LRR 1 The oldest antibodies newly discovered Zeev Pancer & Roy A Mariuzza Figure 1 Assembly of lamprey variable lymphocyte receptors (VLRs), compared with the V(D)J-rearrangement that gives rise to mammalian antibodies. CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS LRR 1 siRNAs with guts otechnology VOLUME 26 by NUMBER 4 APRIL 2008 VLRNATURE genes ofBIOTECHNOLOGY jawless vertebrates are assembled sequential insertion of LRR cassettes from flanking arrays into the incomplete germline gene via gene 4 0 3 Lamprey antibodies provide stable andactivating high-avidity alternatives immunoglobulins. conversion. Jawedmonoclonal vertebrate antibody genes are assembled via recombination gene (RAG)-mediated joining to of immunoglo bulin gene fragments consisting of variable (V), diversity (D) and joining (J) elements, as well as constant (C) exons. The mature antigen receptorsin both cases are expressed on the surfaces of lymphocytes and can be secreted to the plasma. A VLR comprises a set of highly diverse LRR modules capped by disulfide-bonded N-terminal LRR (LRRNT, 24-32 amino acids) and C-terminal LRR (LRRCT, 45-62 amino acids) modules. The 25-residue LRR1 is followed by one to eight 6,7 (Fig. agglutinated anthrax spores 1,000The search for alternatives to immunoglobVLR 1). The selected cassettes are 24-residue LRRVs and then a 16-residue LRR, the connecting peptide (CP). There are two or three hypervariable sites in solvent-exposed positions in each of efficiently than an equivalent am ulin antibodies has led to binding scaffolds sequentially the germthese modules. The invariant portions of VLRs include an N-terminal secretion incorporated peptide (SP) and into an 81-residue C terminus that contains a threonine/prolineof Denmark - DTU richsuch stalk (33 acids) and a glycosyl phosphatidylinositol (GPI)gene membrane anchorage tethers the VLRTechnical to the lyUniversity mphocyte surface. Seven mouse monoclonal antibody, demo as amino lipocalins, fibronectins, ankyrin line framework to motif, formwhich the functional Department of systems biology cysteines in the 22-residue hydrophobicdomains C-terminal1.domain participate in This VLR oligomerization. repeats and src homology mature VLR. process can generate a vast its high avidity for the antigen. By c But can none of these are natural antigen receptors. Sunday, 14 June 2009 repertoire of VLRs, estimated at over 1014 monomeric form of this VLR that TLRs share a prototypical organization of N-terminal (N) extracellular leucine-rich repeat (LRR) motifs. TLRs are dimerized and the ectodomain forms a horseshoeshaped solenoid. François Leulier & Bruno Lemaitre Nature Reviews Genetics 9, 165-178 (March 2008) Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS TOLL LIKE RECEPTORS CAN RECOGNIZE PATTERNS GENOME DUPLICATIONS 716 Genomes and evolution since the last common ancestor of all jawed (reviewed in [18]). The historical record of genomeevents that is retained in fundamental regulators b of stringent selective constraints is thus erased in th Protostomes of terminal target gene. Echinoderms Sea Tubulins urchin Lamprey, before Cephalochordates Amphioxus Hagfish Cartilaginous Zebrafish, A PufferfIsh Mammals Mouse Reptiles Birds Chick I I 600 400 I ( 200 0 MIllIon years ago C 1996 Current Oplnton I” Genetics & Development Phylogenetic Sunday, 14 June 2009 relationships phyla. (The exact branching among extant deuterostome order of lampreys classes and hagfish the last round of homogenization impossible fish Shark L of the second lawless fish Tunicate I------ and actins-representatives of terminal target gene-are encoded by multiple because they need to be expressed at high leve undergo periodic homogenization by gene conversi cycles of duplication and loss. Homogenization paralogs, by whichever mechanism, erases their mo evolutionary record which renders inference of any Urochordates 800 verte CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fiaure 1 and is a matter third class of terminal target gene comprises ubiquitously expressed, single-copy housekeeping such as manganese superoxide dismutase and the subunits of RNA polymerases. As these genes a required in several copies to maintain a high expression level, they have survived genome duplic merely as single copy genes. In this class of terminal gene, records of past duplications are thus also lost Finally, the fourth class of terminal target g exemplified by the olfactory receptor and immunoglob gene families. These proteins interact with liga environmental origin and potentially unlimited di Structural alterations in the absence of regulatory c allow new duplicates to interact with novel ligands. duplicated Technical paralogsUniversity that ofinteract Denmark with - DTU new ligand positively selected, which has caused o Department of systems biology expansion gene families since the origin of vertebrates and their records of early genome-wide events. GENOME DUPLICATIONS 716 Genomes and evolution since the last common ancestor of all jawed (reviewed in [18]). The historical record of genomeevents that is retained in fundamental regulators b of stringent selective constraints is thus erased in th Protostomes of terminal target gene. Echinoderms Sea Tubulins urchin Lamprey, before Cephalochordates Amphioxus Hagfish Cartilaginous Zebrafish, A PufferfIsh Mammals Mouse Reptiles Birds Chick I I 600 400 I ( 200 0 MIllIon years ago C 1996 Current Oplnton I” Genetics & Development Phylogenetic Sunday, 14 June 2009 relationships phyla. (The exact branching among extant deuterostome order of lampreys classes and hagfish the last round of homogenization impossible fish Shark L of the second lawless fish Tunicate I------ and actins-representatives of terminal target gene-are encoded by multiple because they need to be expressed at high leve undergo periodic homogenization by gene conversi cycles of duplication and loss. Homogenization paralogs, by whichever mechanism, erases their mo evolutionary record which renders inference of any Urochordates 800 verte CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fiaure 1 and is a matter third class of terminal target gene comprises ubiquitously expressed, single-copy housekeeping such as manganese superoxide dismutase and the subunits of RNA polymerases. As these genes a required in several copies to maintain a high expression level, they have survived genome duplic merely as single copy genes. In this class of terminal gene, records of past duplications are thus also lost Finally, the fourth class of terminal target g exemplified by the olfactory receptor and immunoglob gene families. These proteins interact with liga environmental origin and potentially unlimited di Structural alterations in the absence of regulatory c allow new duplicates to interact with novel ligands. duplicated Technical paralogsUniversity that ofinteract Denmark with - DTU new ligand positively selected, which has caused o Department of systems biology expansion gene families since the origin of vertebrates and their records of early genome-wide events. Fish & Shellfish Immunology, Volume 26, Issue 6, June 2009, Pages 843-849 Zhenhui Liu, Lei Li, Hongyan Li, Shicui Zhang, Guangdong Ji and Yanling Sun Technical University of Denmark - DTU Department of systems biology Sunday, 14 June 2009 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS It has recently been demonstrated that this organism contains histocompatibility-relevant genes and lymphocyte immune signaling-relevant genes, i.e., components that may be recruited by adaptive immune processes.