Genome Evolution in Yeast

Genome Evolution in Yeast
Gilles Fischer 27th January 2009 | European Course on

INTRODUCTION: Comparative genomics Yeasts as model organisms GENOME EVOLUTION: DNA duplications Chromosome dynamics Nucleotide composition

A brief introduction to the field of Comparative Genomics
Comparing genomes is a very old idea… DNA carries the genetic information: Avery (1943) and Hershey-Chase (1952) Vendrely and Vendrely (1950): "Il ne fait aucun doute que l'étude systématique de la teneur absolue du noyau en acide désoxyribonucléique, à travers de nombreuses espèces animales puisse fournir des suggestions intéressantes en ce qui concerne le problème de l'évolution" Jacques Monod: "Tout ce qui est vrai pour le colibacille est vrai pour l'éléphant"

quantity of evolutionary changes
A brief introduction to the field of Comparative Genomics identical divergent different time or quantity of evolutionary changes Looking for differences Looking for similarities

quantity of evolutionary changes
A brief introduction to the field of Comparative Genomics identical divergent different time or quantity of evolutionary changes Looking for differences Looking for similarities NEED FOR ADEQUATELY RELATED ORGANSIMS

Bio-informatics Looking for differences Rules governing genome evolution Genome sequences Looking for similarities Mechanistic hypotheses Genetic screens functional genomics Experimental Biology Molecular mechanisms

Bio-informatics Looking for differences Rules governing genome evolution Genome sequences Looking for similarities SMALL GENOMES AND EXPERIMENTALLY TRACTABLE Experimental Biology Genetic screens Molecular mechanisms Mechanistic hypotheses functional genomics

A brief introduction to the field of Yeast Genomics
Organisms with small genomes, phylogenetically related and experimentally tractable = YEASTS Eukaryotic micro-organisms classified in the kingdom Fungi About 1,500 species currently described (only 1% of all yeast) Yeasts are unicellular, typically measuring 3–4 µm in diameter (up to over 40 µm) Saccharomyces cerevisiae used in baking and fermenting alcoholic beverages for thousands of years Other species of yeast, such as Candida albicans, are opportunistic human pathogens Yeasts have recently been used to generate electricity in microbial fuel cells and produce ethanol for the biofuel industry. Yeasts are found in both divisions Ascomycota and Basidiomycota The budding yeasts ("true yeasts") are classified in the Saccharomycotina subphylum

Organisms with small genomes, phylogenetically related and experimentally tractable = YEASTS The Tree of Eukaryotes (Keeling et al., 2005)

Saccharomyces paradoxus Saccharomyces mikatae Saccharomyces cerevisiae Saccharomyces kudriavzevii Saccharomyces bayanus Saccharomyces pastorianus Saccharomyces exiguus Saccharomyces servazzii Saccharomyces castellii Candida glabrata Vanderwaltozyma polyspora Zygosaccharomyces rouxii Lachancea thermotolerans Lachancea waltii Lachancea kluyveri Kluyveromyces lactis Kluyveromyces marxianus Eremothecium gossypii Saccharomycodes ludwigii Brettanomyces bruxellensis Pichia angusta Candida lusitaniae Debaryomyces hansenii Pichia stipitis Pichia sorbitophila Candida guilliermondii Candida tropicalis Candida parapsilosis Lodderomyces elongisporus Candida albicans Candida dubliniensis Arxula adeninivorans Yarrowia lipolytica Schizosaccharomyces pombe Saccharomycotina A brief introduction to the field of Yeast Genomics The first eukaryotic genome sequence: The genome of S. cerevisiae André Goffeau 8 years, 120 labs, 641 people Life with 6000 genes Science (1996)

Saccharomyces paradoxus Saccharomyces mikatae Saccharomyces cerevisiae Saccharomyces kudriavzevii Saccharomyces bayanus Saccharomyces pastorianus Saccharomyces exiguus Saccharomyces servazzii Saccharomyces castellii Candida glabrata Vanderwaltozyma polyspora Zygosaccharomyces rouxii Lachancea thermotolerans Lachancea waltii Lachancea kluyveri Kluyveromyces lactis Kluyveromyces marxianus Eremothecium gossypii Saccharomycodes ludwigii Brettanomyces bruxellensis Pichia angusta Candida lusitaniae Debaryomyces hansenii Pichia stipitis Pichia sorbitophila Candida guilliermondii Candida tropicalis Candida parapsilosis Lodderomyces elongisporus Candida albicans Candida dubliniensis Arxula adeninivorans Yarrowia lipolytica Schizosaccharomyces pombe Saccharomycotina A brief introduction to the field of Yeast Genomics Whole Genome Duplication Gain of Megasatellites Gain of HO gene Gain of mating type cassettes and small centromeres frequent tandem duplications Extensive loss of transposable elements and spliceosomal introns

A brief introduction to the field of Yeast Genomics Genome annotation
5769 5204 4998 5308 5104 5084 6273 6434 # genes 274 207 272 258 231 162 200 510 # tRNA 287 131 167 322 286 175 475 1070 # introns 12,1 12,3 9,8 11,3 10,4 10,7 20,5 size (Mb) # chr 16 13 7 8 6 Genome annotation Saccharomyces cerevisiae Candida glabrata Zygosaccharomyces rouxii Lachancea kluyveri (WashU seq center M. Jonhston) Lachancea thermotolerans Kluyveromyces lactis Debaryomyces hansenii Yarrowia lipolytica

Evolutionary scale A brief introduction to the field of Yeast Genomics
100 * 65 - 60 51 48 amino acid identity % Saccharomyces cerevisiae 100 * 90 70 50 Homo sapiens 100 MYr 100 MYr Candida glabrata Zygosaccharomyces rouxii 450 MYr MYr Lachancea kluyveri Mus musculus Lachancea thermotolerans 550 MYr Takifugu rubripes Tetraodon negroviridis MYr Kluyveromyces lactis Ciona intestinalis Debaryomyces hansenii Yarrowia lipolytica *Dujon et al., et * Jaillon et al., Nature, 2004 Berbee and Taylor, 2006; James et al., 2006

important level of redundancy (in all eukaryotic phyla)
A brief introduction to the field of Yeast Genomics Genome redundancy 1.40 WGD Saccharomyces cerevisiae 1.35 1.30 mean family size Candida glabrata 1.25 1.20 Zygosaccharomyces rouxii 1.15 1.10 ZYRO DEHA SACE CAGL LAKL LATH KLLA YALI Lachancea kluyveri (WashU seq center M. Jonhston) important level of redundancy (in all eukaryotic phyla) Gene order changes (differential loss of duplicates, translocation breakpoints) several mechanisms of duplication Lachancea thermotolerans Kluyveromyces lactis Debaryomyces hansenii Yarrowia lipolytica Wolfe and Shields, 1997

===> good model organisms to study genome evolution
Small, compact and specialized: small intergenic sequences few transposable elements few introns limited RNA interference Large evolutionary scale High level of genome redundancy Numerous evolutionary novelties in all clades High number of sequenced genomes Yeast Genomes ===> good model organisms to study genome evolution

Most eukaryotic genomes contain high proportion of duplicated genes
Genome evolution: DNA duplications Most eukaryotic genomes contain high proportion of duplicated genes S. c. A. t. C. e. D. m. H. s. s. duplication Duplicated Genes % 65% 49% 40% 50% Conservation Pseudogenization Neofunctionalization Degeneration Complementation Loss of function (most frequent fate) Gain of a new function Gene dosage increase Genetic robustness Specialization of the 2 copies ===> Strong evolutionary potential

Adaptative value of DNA duplications:
Genome evolution: DNA duplications Adaptative value of DNA duplications: Adaptation to sulfate-limited conditions in chemostats for 200 generations: CGH SDs containing between 1 to 22 genes No homology at the junctions (microhomologies) Gresham et al., PLoS Genet 2008

??? A duplication assay: Genome evolution: DNA duplications and so on…
XV and so on… RPL20B XIII 3days - YPD - 30° RPL20A ==> WT growth rate ??? RPL20B ==> WT growth rate So, to recover spontaneous SD events, independent cultures are propagated through serial transfer and samples are regularly plated until the apparence of large colonies on the plate. These large colonies are then subcloned and analysed at the molecular level. RPL20B XV XIII ==>slow growth rpl20A∆ délétion

Molecular characterization of segmental duplications:
A duplication assay: Genome evolution: DNA duplications Molecular characterization of segmental duplications: I VI III IX V - VIII XI X XIV II V, XIII VII, XV IV - XII XV Karyotype Hybridization RPL20B Comparative Genomic Hybridization 143 kb RPL20B Molecular combing direct tandem Each of the fast growing revertant is karyotpyes by pulsed field gel and as you can see on this picture we can detect large modifications in the karyotypes. Here chromsome XV which contains RPL20B is clearly bigger in the revertant than in the WT. Then we performed CGH to estimate the precise extent of the duplicated segment. These duplications were also mapped by molecular combing, in this case we see that the 2 copies are organized as a direct tandem. And finally we PCR amplified and sequenced the junctions. PCR and sequence Despite the selection of a single gene duplication event, only large segmental duplications were recovered

rate of SDs (/cell/division)
Molecular mechanisms: Genome evolution: DNA duplications strain rate of SDs (/cell/division) type of SDs breakpoint sequences (%) Intra-chromosomal Inter-chromosomal LTRs (300bp) microhomologies (2 to 11 bp) microsatellites (poly A/T or répét trinucleotides) WT 10-7 (1) 42 6 48 52 T 5 10 15 20 25 30 35 40 time (min) Lately replicated regions tRNAs LTRs microsatellites a connection with replication? Raghuraman et al. Science, 2001 pol32∆ (<0.07) - - - - REPLICATION I’d like now to show you few important results of the genetic requirements of SD formation first, in WT, the rate of spontaneous SD formation is 10-7 events per cell and per division which is very high and represents only the duplication events that encompass rpl20B on the right arm of chrimosome XV which means that at the genome wide scale SD must be very frequent in yeast culutres. clb5∆ 7x 10-5 (730) 66 3 62 38 CPT 3 x 10-5 (320) 22 54 56 rad52∆ 3 x 10-7 (3) 70 1 100 DSB REPAIR rad52∆ rad1∆ dnl4∆ 8 x 10-8 (0.8) 15 100 Koszul et al. EMBO J., 2004

Replication-based mechanisms strain rate of SDs (/cell/division) type of SDs breakpoint sequences (%) microhomologies microsatellites Intra-chromosomal Inter-chromosomal LTRs WT 10-7 (1) 42 6 48 52 clb5∆ 7x 10-5 66 3 62 38 (730) Clb5 defect in the firing of late replication origins (Schwob et al , 1993) S-phase lasts twice longer (Epstein et al, 1992) Rad9-dependent activation of the replication checkpoint indicative of DNA damages (Gibson et al, 2004) RPL20B lies in Clb5-dependent region (CDR; McCune et al, 2008) replication perturbations strongly induce SD formation Bloom and Cross, 2007 Pol32 Nick McElhinny, Cell 2008 pol32∆ - (<0.07) Pol32 is required for initiating BIR reaction (Lydeard et al, 2007) SDs are generated through replication-based mechanisms I’d like now to show you few important results of the genetic requirements of SD formation first, in WT, the rate of spontaneous SD formation is 10-7 events per cell and per division which is very high and represents only the duplication events that encompass rpl20B on the right arm of chrimosome XV which means that at the genome wide scale SD must be very frequent in yeast culutres.

Replication-based mechanisms strain rate of SDs (/cell/division) type of SDs breakpoint sequences (%) microhomologies microsatellites Intra-chromosomal Inter-chromosomal LTRs WT 10-7 (1) 42 6 48 52 CPT 3 x 10-5 22 54 56 (320) CPT Top1 Top1 =>broken forks promote SD formation Broken forks as precursor lesions leading to SDs I’d like now to show you few important results of the genetic requirements of SD formation first, in WT, the rate of spontaneous SD formation is 10-7 events per cell and per division which is very high and represents only the duplication events that encompass rpl20B on the right arm of chrimosome XV which means that at the genome wide scale SD must be very frequent in yeast culutres.

The DSB repair pathways
Dnl4 NHEJ Resection HR Rad52 Rad1 pas d’homologies, religature simple Rad51 Pol32 MMEJ SSA BIR Microhomologies (5-12pb) >30pb d’homologies SDSA DSBR 23

Two different replication-based mechanisms strain rate of SDs (/cell/division) type of SDs breakpoint sequences (%) microhomologies microsatellites Intra-chromosomal Inter-chromosomal LTRs WT 10-7 (1) 42 6 48 52 HR-dependent rad52∆ 3 x 10-7 70 1 100 (3) => ====> HR-independent => HR-mediated SDs result from BIR Rad51-independent => Non HR-mediated SDs result from ? I’d like now to show you few important results of the genetic requirements of SD formation first, in WT, the rate of spontaneous SD formation is 10-7 events per cell and per division which is very high and represents only the duplication events that encompass rpl20B on the right arm of chrimosome XV which means that at the genome wide scale SD must be very frequent in yeast culutres.

X Dnl4 Resection X X Rad52 Rad1 25

MMIR: microhomology microsatellite-induced replication strain rate of SDs (/cell/division) type of SDs breakpoint sequences (%) microhomologies microsatellites Intra-chromosomal Inter-chromosomal LTRs WT 10-7 (1) 42 6 48 52 rad52∆ 3 x 10-7 (3) 70 1 100 rad52∆ rad1∆ dnl4∆ 8 x 10-8 15 100 (0.8) SD are still being formed in the absence of all known DSB repair pathways existence of a new DSB repair pathway? HR requires Rad52 MMEJ requires Rad1 NHEJ requires Dnl4 Sequences found at breakpoints: microhomologies between 2 and 11 bp poly (A/T)13-23 trinucleotide repeats (GTT)3-20 I’d like now to show you few important results of the genetic requirements of SD formation first, in WT, the rate of spontaneous SD formation is 10-7 events per cell and per division which is very high and represents only the duplication events that encompass rpl20B on the right arm of chrimosome XV which means that at the genome wide scale SD must be very frequent in yeast culutres. Formation of chimeric genes at breakpoints (in 13 out of 26 junctions) Extremely high density of microhomologies and microsatelites in the genome often intragenic

X Dnl4 Resection X X Rad52 Rad1 27

X Dnl4 Resection X X Rad52 Rad1 A new pathway? MMIR Microhomology/microsatellites Induced Replication - independent from all known DSB repair pathways (HR, NHEJ, MMEJ) - dependent from Pol32 - Replication template switching between microhomologies and microsatellites 28

Conclusions Genome evolution: DNA duplications
SDs are spontaneously generated at high frequency: 10-7 SD/cell/division for the RPL20B locus SDs arise from two alternative replication-based mechanisms: BIR and MMIR MMIR represents a new mechanism different from known DSB repair pathways (HR, NHEJ): between microhomologie (between 2 to 11 nt) and microsatellites (poly A/T, trinucleotide repeats) independent from Rad52 requires Pol32 MMIR induces the formation of chimerical genes at the rearrangement junctions

In human, FoSTeS/MMBIR:
Genome evolution: DNA duplications In human, FoSTeS/MMBIR: Hastings et al, Nature Review Genetics, 2009 Complex structural variations: - Lissencephaly (Nagamani et al., J. Med Genet 2009) - Miller-Dieker syndrome - Charcot-Marie-Tooth disease (Lupski and Chance, 2005) - Pelizaeus Merzbacher disease (Lee et al., Cell 2007) - XLMR syndrome (Bauters et al., Genome Res 2008) - SDs and CNVs (Kim et al., Genome Res 2008)

Genome evolution: Chromosome Dynamics
Duplications: high evolutionary potential (creation of new genes, adaptation, specialization,…) Translocations, inversions, deletions: very low evolutionary potential? (Loss of genes, deregulation of gene expression, modification of sub-nuclear architecture,…) Species 1 translocations Inversions duplications deletions rates of rearrangements Species 2 # x #

Yarrowia lipolytica S. serevisiae S. bayanus Candida glabrata Lachancea kluyveri Debaryomyces hansenii Kluyveromyces lactis Lachancea thermotolerans Zygosaccharomyces rouxii Sensu stricto S. paradoxus S. kudriavzevii S. cariocanus S. mikatae S. bayanus S. cerevisiae Saccharomyces sensu stricto complex: - monophyletic group - very closely related species - hybrids viable but sterile - 16 chromosomes

S. paradoxus S. kudriavzevii S. cariocanus S. mikatae S. bayanus S. cerevisiae only few translocations: low reorganization recombination between repeated sequences no chromosomal speciation variable rate of rearrangements? S. cerevisiae S. paradoxus S. cariocanus S. mikatae S. kudriavzevii S. bayanus (4) (0) (2) (0) (4) S. cerevisiae S. paradoxus S. kudriavzevii S. mikatae S. cariocanus S. bayanus Fischer et al. , Nature 2000

S. cerevisiae S. bayanus C. glabrata K. lactis D. hansenii
Genome evolution: Chromosome Dynamics S. cerevisiae S. bayanus C. glabrata K. lactis D. hansenii Y. lipolytica Yarrowia lipolytica S. serevisiae S. bayanus Candida glabrata Lachancea kluyveri Debaryomyces hansenii Kluyveromyces lactis Lachancea thermotolerans Zygosaccharomyces rouxii Sensu stricto 8 15 5 7 9 11 13 1 3 5 1 4 6 8 10 12 2 4 6 A D G I J 2 4 5 6 chr VIII 98% 88% 77% 11% 5%

Genome evolution: Chromosome Dynamics S. cerevisiae S. bayanus C. glabrata K. lactis D. hansenii Y. lipolytica 8 15 5 7 9 11 13 1 3 5 1 4 6 8 10 12 2 4 6 A D G I J 2 4 5 6 chr VIII 98% 88% 77% 11% 5%

Genome evolution: Chromosome Dynamics Fischer S. cerevisiae S. bayanus C. glabrata K. lactis D. hansenii Y. lipolytica 8 15 5 7 9 11 13 1 3 5 1 4 6 8 10 12 2 4 6 A D G I J 2 4 5 6 chr VIII F. Brunet 98% 88% 77% Fischer et al. , PLoS Genet 2006

Genome evolution: Chromosome Dynamics S. cerevisiae S. bayanus C. glabrata K. lactis D. hansenii Y. lipolytica 8 15 5 7 9 11 13 1 3 5 1 4 6 8 10 12 2 4 6 A D G I J 2 4 5 6 chr VIII 98% 88% 77% 11% 5%

Genome evolution: Chromosome Dynamics at genome scale:
Saccharomyces cerevisiae S.cerevisiae C. glabrata Mean amino acid identity: 65% comprehensive reshuffling 509 translocations, 104 inversions no homologous chromosomes Candida glabrata Zygosaccharomyces rouxii "UNSTABLE" GENOMES "STABLE" GENOMES Lachancea kluyveri Lachancea thermotolerans L. kluyveri L. thermotolerans moderate reshuffling 91 translocations, 22 inversions large chromosomal segments (up to 670 kb) Mean amino acid identity: 58%

( ( ? Genome evolution: Chromosome Dynamics
Quantitative estimation of the relative genome stability: GOC (gene order conservation) species 1 =5 If yes: +1 If no: 0 # neighboring orthologues ? GOC = Total # orthologues species 2 =5 - GOL : Gene Order Loss = 1 - GOC ( GOL ( - Rate of rearrangements = mean rate Dist phylogénétique Rocha, Trends Genet, 2003,

Rearrangement branch rate S. cerevisiae C. glabrata Z. rouxii K. lactis L. kluyveri L. thermot D. hansenii Species instability scale 0.3 0.4 0.5 0.6 0.7 WGD 1.5 Saccharomyces cerevisiae 2.7 1.3 0.4 Candida glabrata 0.6 Zygosaccharomyces rouxii 1.7 0.3 Lachancea kluyveri (WashU seq center M. Jonhston) 0.4 Lachancea thermotolerans 0.0 0.9 Kluyveromyces lactis 1.7 Debaryomyces hansenii 1.7 Yarrowia lipolytica Fischer et al. , PLoS Genet 2006

moderate massive low Sensu stricto differential gene loss S. serevisiae S. bayanus Candida glabrata Unstable genome Zygosaccharomyces rouxii Lachancea kluyveri (WashU seq center M. Jonhston) Stable genomes Lachancea thermotolerans Kluyveromyces lactis TGA expansion Debaryomyces hansenii No synteny Y. lipolytica

Conclusions Genome evolution: Chromosome Dynamics
High level of chromosome plasticity Hundreds of translocations and inversions Gene order is not very constrained Highly variable rates of chromosome rearrangements between lineages but also within a given lineage Is there a selective advantage associated to these rearrangements? Are they accumulated by genetic drift? usually considered as deleterious few examples of the adaptative role of rearrangements (proliferation of cancer cells (O’Neil and Look, 2007), growth advantage of translocated yeast cells (Colson et al, 2004), adaptative gene loss (Domergue, 2005). Creation of genetic novelties requires chromosome plasticity?

not in yeast? > < Genome evolution: Nucleotide composition
Base substitution mutations: C T transitions : cytosine deamination Kreutzer and Essigmann, PNAS, 1998 G T transversions : 8-oxo-guanine Shibutani et al., Nature, 1991 Global AT-enrichment GC% Saccharomyces cerevisiae 38.3 Candida glabrata 38.8 Zygosaccharomyces rouxii 39.1 Lachancea kluyveri 41.5 Lachancea thermotolerans 47.3 Kluyveromyces lactis 38.8 Marsolier-Kergoat and Yeramian, Genetics, 2009 not in yeast? Biased Gene Conversion (BGC): Global GC-enrichment AT GC mutations Duret and Galtier, Annu Rev Genomics Human Genet, 2009 Eremothecium gossypii 52.0 > Debaryomyces hansenii 36.3 < Yarrowia lipolytica 49.0 The Génolevures Consortium, Genome Res., 2009

Lachancea thermotolerans
B C D E F G H 47.3 Lachancea thermotolerans GC% 80 60 40 39.1 20 1 2 3 4 5 6 7 8 9 10 Mb A B C D E F G Zygosaccharomyces rouxii A B C D E F G H 1 2 3 4 5 6 7 8 9 10 Mb 11 20 40 60 80 GC% Lachancea kluyveri 41.5 52.9 C-left 1 Mb

DNA RNA Protein Genome evolution: Nucleotide composition 46.1 37.4
GC% in C-left: 46.1 37.4 54.2 42.0 46.8 36.5 global GC increase GC% out of C-left: RNA 1st 2nd 3rd AAAAAA 53.3 46.4 41.0 37.0 68.3 42.7 strong bias in codon usage GC% in C-left: GC% out of C-left: Protein A G P R I N K F 84 72 11 16 GC% in synonymous codons 1.3 1.2 1.1 0.7 0.8 0.9 relative use in C-left bias in protein composition Payen et al., Genome Res., 2009

Phylogeny: Genome evolution: Nucleotide composition
19 families (4631 residues) in C-left E. gossypii K. lactis L. thermotolerans L. waltii L. kluyveri Z. rouxii C. glabrata S. cerevisiae Alignments of universally conserved proteins : 17 families (6688 residues) outside C-left 100 100 100 100 0.05 96 100 100 100 100 98 C-left has the same phylogentic origin than the rest of the genome Payen et al., Genome Res., 2009

Synteny: Genome evolution: Nucleotide composition
LAWA_S33 LAWA_S27 LAWA_S56 LAWA_S55 670 kb LAKL_C LATH_F LATH_G LATH_C LATH_E LATH_A C-left share a common ancestral origin with the genomes of L. waltii (LAWA) and L. thermotolerans (LATH)

Replication: G1 S G2 Genome evolution: Nucleotide composition
- Design of custom microarrays (Agilent 2 x 105k): 200bp fragments G1 S G2 DNACy3 DNACy5 - Time course analysis of copy number variation during S-phase:

Genome evolution: Nucleotide composition
Replication: ChrA ChrB

Genome evolution: Nucleotide composition
Replication: ChrC ChrD

of genome nucleotide composition
Conclusions Genome evolution: Nucleotide composition L. kluyveri offers a unique opportunity to understand the mechansims of evolution of genome nucleotide composition Global GC increase (codon usage bias and protein composition bias) harbors a normal gene density Phylogenetic origin consistent with the rest of the genome presents a very high level of synteny conservation with sister species genomes encompasses the MAT locus but has lost the silent cassettes HMR and HML is devoid of Transposable Elements (203 insertions in the rest of the genome) harbors the same compositional bias in all 11 L. kluyveri strains tested The replication program is modified (more origins and delayed firing) => a cause or a consequence of the unusual GC composition? Meiotic recombination and BGC?

Merci - Génolevures consortium:
- Unité de Génétique Moléculaire des Levures, Institut Pasteur Celia Payen Romain Koszul - Unité de Génomique des Microorganismes, équipe Biologie des Génomes Nicolas Agier Guénola Drillon - Génolevures consortium: Jean-Luc Souciet Univ. Louis Pasteur, Strasbourg - Centre National de Séquençage, Evry Jean Weissenbach, Patrick Winker - Génopole Pasteur-Ile de France Christiane Bouchier, Lionel Frangeul - Plateforme Puces ADN, Génopole Pasteur Odile Sismeiro, Jean-Yves Coppé

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