Evolutionary Forces in Mycobacterium tuberculosis
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1 Evolutionary Forces in Mycobacterium tuberculosis Sébastien Gagneux,, PhD 22 nd September, 2010
2 Molecular Typing of Mtb What is the question? (i.e. why are you genotyping your strains?)
3 Use the Ideal Marker for Each Question Pragmatic / public health ( traditional Molepi) MIRU-VNTR / spoligo vs Strain classification (e.g. phenotypic associations) LSPs / SNPs vs Evolutionary studies (e.g. phylogenetics) DNA seq Comas et al PLoS ONE 4: e7815
4 Comparison of 4 Global Phylogenies of Mtb Gagneux et al Baker a et al b 12can M. canettii Indo-Oceanic 239 TbD East-Asian East-African-Indian Middle East pks 15/1?7bp 7bp Americas Europe Euro-American 219 H37Rv-like 174 West Africa South Africa 724 Central Africa West-African , 8, 10 Gutacker et al c West-African-2 M. bovis lineage d et al Filliol Gagneux & Small Lancet ID :
5 Global Biogeography of Mtb Gagneux et al PNAS 103:
6 Comparative DNA Sequencing of Mtb Two Data Sets: MLSA: 89 genes, 108 strains Illumina seq: 22 genomes Rv0164 Rv0129c Rv0079 Rv0040c Rv0005 Rv0006 Rv0287 Rv0251c Rv0407 Rv0467 Rv0009 Rv3904c Rv3905c Rv3908 Rv3890c Rv3891c Rv0410c Rv0413 Rv0288 Rv0569 Rv0475 Rv0429c Rv3872 Rv3874 Rv3875 Rv3804c Rv3763 Rv3589 Rv3547 Rv3407 Rv3354 Rv0652 Rv3418c Rv3221c Rv3261 Rv0798c Rv3262 Mycobacterium tuberculosis H37Rv Rv3132c Rv3133c Rv3126c Rv3129 Rv0909 Rv0934 Rv2985 Rv2957 Rv2958c Rv2959c Rv2962c Rv bps Rv2949c Rv2952 Rv2924c Rv2875 Rv1072 Rv2873 Rv1160 Rv1174c Rv1173 Rv1184c Rv2687c Rv1195 Rv2744c Rv2627c Rv2686c Rv2628 Rv1305 Rv2462c Rv2626c Rv1316c Rv1411c Rv1738 Rv1827 Rv1886c Rv1984c Rv2007c Rv2031c Rv2450c Rv2389c Rv2330c Rv1636 Rv1733c Rv1813c Rv1884c Rv1926c Rv1980c Rv1996 Rv2030c Rv2032 Rv2185c Hershberg et al PLoS Biology 6: e311 Comas et al Nature Genetics 42:
7 LSPs (Gagneux et al. 2006) MLSA (Hershberg et al. 2008) Comas & Gagneux 2009 PLoS Pathogens 5:
8 Global Phylogeny of MTBC ancient (TbD + ) Animal Strains 108 strains modern (TbD - ) ~70kbp/strain Parsimony HI = Hershberg et al PLoS Biology 6: e311
9 22 Mtb Genomes Comas et al Nature Genetics 42:
10 Nature of DNA Sequence Diversity Understanding dn/ds nsnp: : change in amino acid ssnp: : no change in amino acid dn = nsnps observed / nsnps possible ds = ssnps observed / ssnps possible If dn/ds < 1, purifying selection If dn/ds > 1, diversifying selection
11 dn/ds is unusually high in Mtb Mtb: 0.63 (~ 2/3 nsnps!) E. coli: 0.09 Other mycobacteria: ~ 0.16 M. canettii: 0.18 Hershberg et al PLoS Biology 6: e311 Comas et al Nature Genetics 42:
12 Bottlenecks in the Life History of Mtb Historical: Transmission: 1 to 10 bacteria
13 Mtb Has a Small Effective Population Size Natural Selection Genetic Drift Reduced Purifying Selection in Mtb
14 Global Phylogeography of Mtb Comas et al Nature Genetics 42: Gagneux et al PNAS 103: Gagneux & Small 2007 Lancet Infect Dis 7: Mtb originated in Africa
15 Out-of-and-back-to-Africa of Mtb ~50,000 years ago < 500 years ago Hershberg et al PLoS Biology 6:e311
16 Long-standing Association Between Mtb and Humans Mtb originated in Africa Diversity shaped by human migration & demography Mtb has phylogeographic structure Host-pathogen co-evolution?
17 Host-Pathogen Co-Evolution Evolutionary arms race Immune evasion Examples: HIV HCV Plasmodium Neisseria Immune Evasion in Mtb?
18 22 Genomes - Three Gene Sets: 3,990 genes in H37Rv 3, PE/PPE/mobile 760 Essential 2,879 Non-essential 78 T-cell Antigens (491 Epitopes)
19 Two Measures of Evolutionary Conservation Average Nucleotide Diversity (π)( dn/ds
20 Essential Genes Are More Conserved than Non-essential Genes p < p < Nucleotide Diversity nucleotide diversity Nonessential Essential Nonessential dn/ds dn/ds essential nonessential Essential gene category Comas et al Nature Genetics 42:
21 Antigens Are NOT More Diverse N. S. Nucleotide Diversity Essential Nonessential Antigens
22 Antigens Are Equally Conserved N. S dn/ds dn/ds Essential Nonessential Antigens essential non-essential antigens gene category
23 Antigens Consist of Epitopes and Non-Epitopes Epitopes Non-Epitopes
24 Epitopes are More Conserved than Non-epitopes p < dn/ds dn/ds Epitopes epitope Epitopes gene category nonepitope Non-Epitopes
25 Epitopes Most Conserved dn/ds dn/ds Genome genome essential nonessential epitopes Essential gene category Nonessential Epitopes Comas et al Nature Genetics 42:
26 Conclusions Mtb is more diverse Random genetic drift ( chance( chance ) Longstanding host-pathogen association T-cell epitopes are hyperconserved
27 Proposal for New Nomenclature for Main MTBC Lineages (excl. Animal TB) Coscolla & Gagneux Drug Discovery Today 2010 in press
28 Swiss TPH, Basel Sonia Borrell Bijaya Malla Mireia Coscollá Funding: MRC, NIH/NIAID, Royal Society, SNSF David Stucki MRC NIMR, London Collaborators Joel Ernst Douglas Young Stefan Niemann Peter Small James Galagan Dmitri Petrov Marcus Feldman Iñaki Comas Tembi Huna Graham Rose
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