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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. Find IS-related proteins
2. Determine orthologies
3. Pfam annotation
4. Panther annotation
5. 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
548
967
IRIS only
GO only
IRIS & GO
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) Human
Human, mouse, rat, chicken
Hs, Mm, Rn, Gg
Z>20 RH>0.5*QL
~25,000 groups
PHYLOME
SELECTION OF HOMOLOGS
ALIGNMENTS AND TREES
PROTEOME
PROTEOMES
TREE SCANNING
LIST Hs-Mm pairsHs-Rn pairsHs-Gg pairsMm-Rn pairsMm-Gg pairsRn-Gg pairs
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 - - - -
BBHpfam Hs Mm Rn Gg
PGTpfam Hs Mm Rn Gg
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
62%11%
13%
14%
Hs
Hs+Mm
Hs+Mm+Rn
Hs+Mm+Rn+Gg
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 - - - -
BBHpanther Hs Mm Rn Gg
PGTpanther Hs Mm Rn Gg
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
39%
15%
20%
26%
Hs
Hs+Mm
Hs+Mm+Rn
Hs+Mm+Rn+Gg
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