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The evolution of the immune system in chicken and higher vertebrates @ Organon, Oss 2005-09-20 Tim Hulsen Biorange Project SP3.2.2 • Chicken immunosystem project is part of WP1, “Translational Medicine through Comparative Genomics and Integration” • Partners: – Animal Breeding and Genetics Group, Wageningen UR (Prof. dr. Martien Groenen) – Avian Cytokines Group, Institute for Animal Health, Compton (UK) (Prof. dr. Pete Kaiser) • Jack Leunissen (WUR) also part of WP1 M. Groenen: chicken sequencing Kaiser: chicken immune system Introduction • Goal: developing an insight in the recent evolution of the immune system • Usage of a more distant species: chicken (recently sequenced) • Support by experimental data Overview 1. 2. 3. 4. 5. Find IS-related proteins Determine orthologies Pfam annotation Panther annotation Zooming in Step 1: Find IS-related proteins • IRIS: “Immunogenetic Related Information Source” • number of immune genes: 1562 (out of 21389 in LocusLink) • percentage of genome related to immunity: 7.30% • 1562 LocusLink proteins mapped to our Protein World set: 1381 proteins Step 1: Find IS-related proteins Step 1: Find IS-related proteins • GO: Gene Ontology • collaborative effort to address the need for consistent descriptions of gene products in different databases • Checked human GO annotation for certain terms: “immunology”,”cytokine”,etc. • 1515 proteins in human Potein World set Step 1: Find IS-related proteins • Result: – 1381 proteins through IRIS – 1515 proteins through GO – 1929 proteins total 414 IRIS only GO only IRIS & GO 967 548 Step 2: Determine orthologies • Study evolution from chicken (Gg) to rat (Rn), mouse (Mm) and human (Hs): – – – – – – Hs<->Mm Hs<->Rn Hs<->Gg Mm<->Rn Mm<->Gg Rn<->Gg • Two methods: Best Bidirectional Hit (BBH) and PhyloGenetic Tree (PGT) Best Bidirectional Hit (BBH) • Very easy and quick • Human protein (1) SW best hit in mouse/rat (2) • Mouse/rat protein (2) SW best hit in human (3) • If 3 equals 1, the human and mouse/rat protein are considered to be orthologs Step 2: Determine orthologies BBH Hs Mm Rn Gg Hs 1929 1145 1046 704 Mm - - 863 345 Rn - - - 488 Gg - - - - PhyloGenetic Tree (PGT) PROTEOME Human PROTEOMES Human, mouse, rat, chicken SELECTION OF HOMOLOGS Hs, Mm, Rn, Gg LIST Hs-Mm pairs ALIGNMENTS AND TREES TREE SCANNING PHYLOME Z>20 RH>0.5*QL Hs-Rn pairs Hs-Gg pairs Mm-Rn pairs Mm-Gg pairs Rn-Gg pairs ~25,000 groups Step 2: Determine orthologies PGT Hs Mm Rn Gg Hs 1929 2301 1819 1129 Mm - - 2873 2087 Rn - - - 2142 Gg - - - - Step 3: Pfam annotation • Pfam: “Protein families database of alignments and HMMs” • collection of protein families and domains • Pfam contains multiple protein alignments and profile-HMMs of these families • 75% of protein sequences have at least one match to Pfam • 1700 IS-related proteins mapped to 584 Pfam families (2814 mappings) Step 3: Pfam annotation BBH Hs Mm Rn Gg PGT Hs Mm Rn Gg Hs 1929 1145 1046 704 Hs 1929 2301 1819 1129 Mm - - 863 345 Mm - - 2873 2087 Rn - - - 488 Rn - - - 2142 Gg - - - - Gg - - - - Hs Mm Rn Gg BBH pfam Hs Mm Rn Gg PGT pfam Hs 1776 1069 974 639 Hs 1776 2135 1700 1040 Mm - - 795 312 Mm - - 2846 2070 Rn - - - 442 Rn - - - 2125 Gg - - - - Gg - - - - Step 3: Pfam annotation 14% 13% Hs Hs+Mm Hs+Mm+Rn Hs+Mm+Rn+Gg 11% 62% Step 4: Panther annotation • • • • • PANTHER: “Protein ANalysis THrough Evolutionary Relationships” designed to classify proteins (and their genes) in order to facilitate high-throughput analysis proteins have been classified according to families and subfamilies, molecular functions, biological processes, pathways contains over 6683 protein families, divided into 31,705 functionally distinct protein subfamilies 1872 IS-related proteins mapped to 970 Panther families (4667 subfamilies, 14737 mappings) Step 4: Panther annotation BBH Hs Mm Rn Gg PGT Hs Mm Rn Gg Hs 1929 1145 1046 704 Hs 1929 2301 1819 1129 Mm - - 863 345 Mm - - 2873 2087 Rn - - - 488 Rn - - - 2142 Gg - - - - Gg - - - - Hs Mm Rn Gg BBH panther Hs Mm Rn Gg PGT panther Hs 1872 1125 1029 688 Hs 1872 2266 1793 1118 Mm - - 846 339 Mm - - 2729 1970 Rn - - - 481 Rn - - - 2008 Gg - - - - Gg - - - - Step 4: Panther annotation 26% 39% Hs Hs+Mm Hs+Mm+Rn Hs+Mm+Rn+Gg 20% 15% Step 5: Zooming in • Which families are ‘new’ in human? • Which orthologs have a different domain structure through evolution? • Which human proteins don’t have orthologs in the other species? • Any other interesting stuff Future directions • Include paralogs in our analysis (makes possible checking which families only exist in mouse/rat/chicken) • Combine our findings with research at WUR: synteny between human and chicken • Take a look at ratio of non-synonymous to synonymous substitutions (dN/dS) Credits • NV Organon: – Peter Groenen – Wilco Fleuren • Wageningen UR: – Martien Groenen – Hindrik Kerstens • Compton (UK): – Pete Kaiser