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A fast and agnostic method for bacterial genome-wide association studies: Bridging the gap between k-mers and genetic events

Identifieur interne : 001001 ( Pmc/Curation ); précédent : 001000; suivant : 001002

A fast and agnostic method for bacterial genome-wide association studies: Bridging the gap between k-mers and genetic events

Auteurs : Magali Jaillard [France] ; Leandro Lima [France] ; Maud Tournoud [France] ; Pierre Mahé [France] ; Alex Van Belkum [France] ; Vincent Lacroix [France] ; Laurent Jacob [France]

Source :

RBID : PMC:6258240

Abstract

Genome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or detailed assessment of marker effect. Recently, alignment-free methods based on k-mer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are sometimes hard to interpret. Here we introduce DBGWAS, an extended k-mer-based GWAS method producing interpretable genetic variants associated with distinct phenotypes. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is alignment-free and only requires a set of contigs and phenotypes. In particular, it does not require prior annotation or reference genomes. It produces subgraphs representing phenotype-associated genetic variants such as local polymorphisms and mobile genetic elements (MGE). It offers a graphical framework which helps interpret GWAS results. Importantly it is also computationally efficient—experiments took one hour and a half on average. We validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in Mycobacterium tuberculosis, and genes acquired by horizontal transfer in Staphylococcus aureus and Pseudomonas aeruginosa—along with their MGE context. It also enabled us to formulate new hypotheses involving genetic variants not yet described in the antibiotic resistance literature. An open-source tool implementing DBGWAS is available at https://gitlab.com/leoisl/dbgwas.


Url:
DOI: 10.1371/journal.pgen.1007758
PubMed: 30419019
PubMed Central: 6258240

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PMC:6258240

Le document en format XML

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<p>Genome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or detailed assessment of marker effect. Recently, alignment-free methods based on k-mer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are sometimes hard to interpret. Here we introduce DBGWAS, an extended k-mer-based GWAS method producing interpretable genetic variants associated with distinct phenotypes. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is alignment-free and only requires a set of contigs and phenotypes. In particular, it does not require prior annotation or reference genomes. It produces subgraphs representing phenotype-associated genetic variants such as local polymorphisms and mobile genetic elements (MGE). It offers a graphical framework which helps interpret GWAS results. Importantly it is also computationally efficient—experiments took one hour and a half on average. We validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in
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<italic>Staphylococcus aureus</italic>
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<author>
<name sortKey="Farhat, Mr" uniqKey="Farhat M">MR Farhat</name>
</author>
<author>
<name sortKey="Shapiro, Bj" uniqKey="Shapiro B">BJ Shapiro</name>
</author>
<author>
<name sortKey="Kieser, Kj" uniqKey="Kieser K">KJ Kieser</name>
</author>
<author>
<name sortKey="Sultana, R" uniqKey="Sultana R">R Sultana</name>
</author>
<author>
<name sortKey="Jacobson, Kr" uniqKey="Jacobson K">KR Jacobson</name>
</author>
<author>
<name sortKey="Victor, Tc" uniqKey="Victor T">TC Victor</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sheppard, Sk" uniqKey="Sheppard S">SK Sheppard</name>
</author>
<author>
<name sortKey="Didelot, X" uniqKey="Didelot X">X Didelot</name>
</author>
<author>
<name sortKey="Meric, G" uniqKey="Meric G">G Meric</name>
</author>
<author>
<name sortKey="Torralbo, A" uniqKey="Torralbo A">A Torralbo</name>
</author>
<author>
<name sortKey="Jolley, Ka" uniqKey="Jolley K">KA Jolley</name>
</author>
<author>
<name sortKey="Kelly, Dj" uniqKey="Kelly D">DJ Kelly</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Alam, Mt" uniqKey="Alam M">MT Alam</name>
</author>
<author>
<name sortKey="Petit, Ra" uniqKey="Petit R">RA Petit</name>
</author>
<author>
<name sortKey="Crispell, Ek" uniqKey="Crispell E">EK Crispell</name>
</author>
<author>
<name sortKey="Thornton, Ta" uniqKey="Thornton T">TA Thornton</name>
</author>
<author>
<name sortKey="Conneely, Kn" uniqKey="Conneely K">KN Conneely</name>
</author>
<author>
<name sortKey="Jiang, Y" uniqKey="Jiang Y">Y Jiang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Chewapreecha, C" uniqKey="Chewapreecha C">C Chewapreecha</name>
</author>
<author>
<name sortKey="Marttinen, P" uniqKey="Marttinen P">P Marttinen</name>
</author>
<author>
<name sortKey="Croucher, Nj" uniqKey="Croucher N">NJ Croucher</name>
</author>
<author>
<name sortKey="Salter, Sj" uniqKey="Salter S">SJ Salter</name>
</author>
<author>
<name sortKey="Harris, Sr" uniqKey="Harris S">SR Harris</name>
</author>
<author>
<name sortKey="Mather, Ae" uniqKey="Mather A">AE Mather</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Earle, Sg" uniqKey="Earle S">SG Earle</name>
</author>
<author>
<name sortKey="Wu, Ch" uniqKey="Wu C">CH Wu</name>
</author>
<author>
<name sortKey="Charlesworth, J" uniqKey="Charlesworth J">J Charlesworth</name>
</author>
<author>
<name sortKey="Stoesser, N" uniqKey="Stoesser N">N Stoesser</name>
</author>
<author>
<name sortKey="Gordon, Nc" uniqKey="Gordon N">NC Gordon</name>
</author>
<author>
<name sortKey="Walker, Tm" uniqKey="Walker T">TM Walker</name>
</author>
</analytic>
</biblStruct>
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<author>
<name sortKey="Lees, Ja" uniqKey="Lees J">JA Lees</name>
</author>
<author>
<name sortKey="Vehkala, M" uniqKey="Vehkala M">M Vehkala</name>
</author>
<author>
<name sortKey="V Lim Ki, N" uniqKey="V Lim Ki N">N Välimäki</name>
</author>
<author>
<name sortKey="Harris, Sr" uniqKey="Harris S">SR Harris</name>
</author>
<author>
<name sortKey="Chewapreecha, C" uniqKey="Chewapreecha C">C Chewapreecha</name>
</author>
<author>
<name sortKey="Croucher, Nj" uniqKey="Croucher N">NJ Croucher</name>
</author>
</analytic>
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<author>
<name sortKey="Jaillard, M" uniqKey="Jaillard M">M Jaillard</name>
</author>
<author>
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</author>
<author>
<name sortKey="Cady, Kc" uniqKey="Cady K">KC Cady</name>
</author>
<author>
<name sortKey="Creely, D" uniqKey="Creely D">D Creely</name>
</author>
<author>
<name sortKey="Shortridge, D" uniqKey="Shortridge D">D Shortridge</name>
</author>
<author>
<name sortKey="Blanc, B" uniqKey="Blanc B">B Blanc</name>
</author>
</analytic>
</biblStruct>
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<name sortKey="Page, Aj" uniqKey="Page A">AJ Page</name>
</author>
<author>
<name sortKey="Cummins, Ca" uniqKey="Cummins C">CA Cummins</name>
</author>
<author>
<name sortKey="Hunt, M" uniqKey="Hunt M">M Hunt</name>
</author>
<author>
<name sortKey="Wong, Vk" uniqKey="Wong V">VK Wong</name>
</author>
<author>
<name sortKey="Reuter, S" uniqKey="Reuter S">S Reuter</name>
</author>
<author>
<name sortKey="Holden, Mt" uniqKey="Holden M">MT Holden</name>
</author>
</analytic>
</biblStruct>
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<author>
<name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name>
</author>
<author>
<name sortKey="Li, D" uniqKey="Li D">D Li</name>
</author>
<author>
<name sortKey="Zhao, L" uniqKey="Zhao L">L Zhao</name>
</author>
<author>
<name sortKey="Fleming, J" uniqKey="Fleming J">J Fleming</name>
</author>
<author>
<name sortKey="Lin, N" uniqKey="Lin N">N Lin</name>
</author>
<author>
<name sortKey="Wang, T" uniqKey="Wang T">T Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Blair, Jm" uniqKey="Blair J">JM Blair</name>
</author>
<author>
<name sortKey="Webber, Ma" uniqKey="Webber M">MA Webber</name>
</author>
<author>
<name sortKey="Baylay, Aj" uniqKey="Baylay A">AJ Baylay</name>
</author>
<author>
<name sortKey="Ogbolu, Do" uniqKey="Ogbolu D">DO Ogbolu</name>
</author>
<author>
<name sortKey="Piddock, Lj" uniqKey="Piddock L">LJ Piddock</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Haft, Dh" uniqKey="Haft D">DH Haft</name>
</author>
<author>
<name sortKey="Dicuccio, M" uniqKey="Dicuccio M">M DiCuccio</name>
</author>
<author>
<name sortKey="Badretdin, A" uniqKey="Badretdin A">A Badretdin</name>
</author>
<author>
<name sortKey="Brover, V" uniqKey="Brover V">V Brover</name>
</author>
<author>
<name sortKey="Chetvernin, V" uniqKey="Chetvernin V">V Chetvernin</name>
</author>
<author>
<name sortKey="O Eill, K" uniqKey="O Eill K">K O’Neill</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Le Bras, Y" uniqKey="Le Bras Y">Y Le Bras</name>
</author>
<author>
<name sortKey="Collin, O" uniqKey="Collin O">O Collin</name>
</author>
<author>
<name sortKey="Monjeaud, C" uniqKey="Monjeaud C">C Monjeaud</name>
</author>
<author>
<name sortKey="Lacroix, V" uniqKey="Lacroix V">V Lacroix</name>
</author>
<author>
<name sortKey="Rivals, E" uniqKey="Rivals E">É Rivals</name>
</author>
<author>
<name sortKey="Lemaitre, C" uniqKey="Lemaitre C">C Lemaitre</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rahman, A" uniqKey="Rahman A">A Rahman</name>
</author>
<author>
<name sortKey="Hallgrimsd Ttir, I" uniqKey="Hallgrimsd Ttir I">I Hallgrímsdóttir</name>
</author>
<author>
<name sortKey="Eisen, M" uniqKey="Eisen M">M Eisen</name>
</author>
<author>
<name sortKey="Pachter, L" uniqKey="Pachter L">L Pachter</name>
</author>
</analytic>
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<name sortKey="Read, Td" uniqKey="Read T">TD Read</name>
</author>
<author>
<name sortKey="Massey, Rc" uniqKey="Massey R">RC Massey</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Power, Ra" uniqKey="Power R">RA Power</name>
</author>
<author>
<name sortKey="Parkhill, J" uniqKey="Parkhill J">J Parkhill</name>
</author>
<author>
<name sortKey="De Oliveira, T" uniqKey="De Oliveira T">T de Oliveira</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="De Bruijn, N" uniqKey="De Bruijn N">N de Bruijn</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Pevzner, Pa" uniqKey="Pevzner P">PA Pevzner</name>
</author>
<author>
<name sortKey="Tang, H" uniqKey="Tang H">H Tang</name>
</author>
<author>
<name sortKey="Waterman, Ms" uniqKey="Waterman M">MS Waterman</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zhang, W" uniqKey="Zhang W">W Zhang</name>
</author>
<author>
<name sortKey="Chen, J" uniqKey="Chen J">J Chen</name>
</author>
<author>
<name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name>
</author>
<author>
<name sortKey="Tang, Y" uniqKey="Tang Y">Y Tang</name>
</author>
<author>
<name sortKey="Shang, J" uniqKey="Shang J">J Shang</name>
</author>
<author>
<name sortKey="Shen, B" uniqKey="Shen B">B Shen</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Iqbal, Z" uniqKey="Iqbal Z">Z Iqbal</name>
</author>
<author>
<name sortKey="Caccamo, M" uniqKey="Caccamo M">M Caccamo</name>
</author>
<author>
<name sortKey="Turner, I" uniqKey="Turner I">I Turner</name>
</author>
<author>
<name sortKey="Flicek, P" uniqKey="Flicek P">P Flicek</name>
</author>
<author>
<name sortKey="Mcvean, G" uniqKey="Mcvean G">G McVean</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hooper, Dc" uniqKey="Hooper D">DC Hooper</name>
</author>
<author>
<name sortKey="Jacoby, Ga" uniqKey="Jacoby G">GA Jacoby</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lowy, Fd" uniqKey="Lowy F">FD Lowy</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Piton, J" uniqKey="Piton J">J Piton</name>
</author>
<author>
<name sortKey="Petrella, S" uniqKey="Petrella S">S Petrella</name>
</author>
<author>
<name sortKey="Delarue, M" uniqKey="Delarue M">M Delarue</name>
</author>
<author>
<name sortKey="Andre Leroux, G" uniqKey="Andre Leroux G">G André-Leroux</name>
</author>
<author>
<name sortKey="Jarlier, V" uniqKey="Jarlier V">V Jarlier</name>
</author>
<author>
<name sortKey="Aubry, A" uniqKey="Aubry A">A Aubry</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lambert, P" uniqKey="Lambert P">P Lambert</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lambert, T" uniqKey="Lambert T">T Lambert</name>
</author>
<author>
<name sortKey="Ploy, M" uniqKey="Ploy M">M Ploy</name>
</author>
<author>
<name sortKey="Courvalin, P" uniqKey="Courvalin P">P Courvalin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lee, H" uniqKey="Lee H">H Lee</name>
</author>
<author>
<name sortKey="Cho, S" uniqKey="Cho S">S Cho</name>
</author>
<author>
<name sortKey="Bang, H" uniqKey="Bang H">H Bang</name>
</author>
<author>
<name sortKey="Lee, J" uniqKey="Lee J">J Lee</name>
</author>
<author>
<name sortKey="Bai, G" uniqKey="Bai G">G Bai</name>
</author>
<author>
<name sortKey="Kim, S" uniqKey="Kim S">S Kim</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Farhat, Mr" uniqKey="Farhat M">MR Farhat</name>
</author>
<author>
<name sortKey="Sultana, R" uniqKey="Sultana R">R Sultana</name>
</author>
<author>
<name sortKey="Iartchouk, O" uniqKey="Iartchouk O">O Iartchouk</name>
</author>
<author>
<name sortKey="Bozeman, S" uniqKey="Bozeman S">S Bozeman</name>
</author>
<author>
<name sortKey="Galagan, J" uniqKey="Galagan J">J Galagan</name>
</author>
<author>
<name sortKey="Sisk, P" uniqKey="Sisk P">P Sisk</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Flandrois, Jp" uniqKey="Flandrois J">JP Flandrois</name>
</author>
<author>
<name sortKey="Lina, G" uniqKey="Lina G">G Lina</name>
</author>
<author>
<name sortKey="Dumitrescu, O" uniqKey="Dumitrescu O">O Dumitrescu</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Gordon, N" uniqKey="Gordon N">N Gordon</name>
</author>
<author>
<name sortKey="Price, J" uniqKey="Price J">J Price</name>
</author>
<author>
<name sortKey="Cole, K" uniqKey="Cole K">K Cole</name>
</author>
<author>
<name sortKey="Everitt, R" uniqKey="Everitt R">R Everitt</name>
</author>
<author>
<name sortKey="Morgan, M" uniqKey="Morgan M">M Morgan</name>
</author>
<author>
<name sortKey="Finney, J" uniqKey="Finney J">J Finney</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Westh, H" uniqKey="Westh H">H Westh</name>
</author>
<author>
<name sortKey="Hougaard, D" uniqKey="Hougaard D">D Hougaard</name>
</author>
<author>
<name sortKey="Vuust, J" uniqKey="Vuust J">J Vuust</name>
</author>
<author>
<name sortKey="Rosdahl, V" uniqKey="Rosdahl V">V Rosdahl</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Benson, Da" uniqKey="Benson D">DA Benson</name>
</author>
<author>
<name sortKey="Cavanaugh, M" uniqKey="Cavanaugh M">M Cavanaugh</name>
</author>
<author>
<name sortKey="Clark, K" uniqKey="Clark K">K Clark</name>
</author>
<author>
<name sortKey="Karsch Mizrachi, I" uniqKey="Karsch Mizrachi I">I Karsch-Mizrachi</name>
</author>
<author>
<name sortKey="Lipman, Dj" uniqKey="Lipman D">DJ Lipman</name>
</author>
<author>
<name sortKey="Ostell, J" uniqKey="Ostell J">J Ostell</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bi, D" uniqKey="Bi D">D Bi</name>
</author>
<author>
<name sortKey="Xie, Y" uniqKey="Xie Y">Y Xie</name>
</author>
<author>
<name sortKey="Tai, C" uniqKey="Tai C">C Tai</name>
</author>
<author>
<name sortKey="Jiang, X" uniqKey="Jiang X">X Jiang</name>
</author>
<author>
<name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name>
</author>
<author>
<name sortKey="Harrison, Em" uniqKey="Harrison E">EM Harrison</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Palomino, Jc" uniqKey="Palomino J">JC Palomino</name>
</author>
<author>
<name sortKey="Martin, A" uniqKey="Martin A">A Martin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Davis, Jj" uniqKey="Davis J">JJ Davis</name>
</author>
<author>
<name sortKey="Boisvert, S" uniqKey="Boisvert S">S Boisvert</name>
</author>
<author>
<name sortKey="Brettin, T" uniqKey="Brettin T">T Brettin</name>
</author>
<author>
<name sortKey="Kenyon, Rw" uniqKey="Kenyon R">RW Kenyon</name>
</author>
<author>
<name sortKey="Mao, C" uniqKey="Mao C">C Mao</name>
</author>
<author>
<name sortKey="Olson, R" uniqKey="Olson R">R Olson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lees, J" uniqKey="Lees J">J Lees</name>
</author>
<author>
<name sortKey="Galardini, M" uniqKey="Galardini M">M Galardini</name>
</author>
<author>
<name sortKey="Bentley, Sd" uniqKey="Bentley S">SD Bentley</name>
</author>
<author>
<name sortKey="Weiser, Jn" uniqKey="Weiser J">JN Weiser</name>
</author>
<author>
<name sortKey="Corander, J" uniqKey="Corander J">J Corander</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Traore, H" uniqKey="Traore H">H Traore</name>
</author>
<author>
<name sortKey="Fissette, K" uniqKey="Fissette K">K Fissette</name>
</author>
<author>
<name sortKey="Bastian, I" uniqKey="Bastian I">I Bastian</name>
</author>
<author>
<name sortKey="Devleeschouwer, M" uniqKey="Devleeschouwer M">M Devleeschouwer</name>
</author>
<author>
<name sortKey="Portaels, F" uniqKey="Portaels F">F Portaels</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Illakkiam, D" uniqKey="Illakkiam D">D Illakkiam</name>
</author>
<author>
<name sortKey="Shankar, M" uniqKey="Shankar M">M Shankar</name>
</author>
<author>
<name sortKey="Ponraj, P" uniqKey="Ponraj P">P Ponraj</name>
</author>
<author>
<name sortKey="Rajendhran, J" uniqKey="Rajendhran J">J Rajendhran</name>
</author>
<author>
<name sortKey="Gunasekaran, P" uniqKey="Gunasekaran P">P Gunasekaran</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ali Ahmad, A" uniqKey="Ali Ahmad A">A Ali-Ahmad</name>
</author>
<author>
<name sortKey="Fadel, F" uniqKey="Fadel F">F Fadel</name>
</author>
<author>
<name sortKey="Sebban Kreuzer, C" uniqKey="Sebban Kreuzer C">C Sebban-Kreuzer</name>
</author>
<author>
<name sortKey="Ba, M" uniqKey="Ba M">M Ba</name>
</author>
<author>
<name sortKey="Pelissier, Gd" uniqKey="Pelissier G">GD Pélissier</name>
</author>
<author>
<name sortKey="Bornet, O" uniqKey="Bornet O">O Bornet</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Marschall, T" uniqKey="Marschall T">T Marschall</name>
</author>
<author>
<name sortKey="Marz, M" uniqKey="Marz M">M Marz</name>
</author>
<author>
<name sortKey="Abeel, T" uniqKey="Abeel T">T Abeel</name>
</author>
<author>
<name sortKey="Dijkstra, L" uniqKey="Dijkstra L">L Dijkstra</name>
</author>
<author>
<name sortKey="Dutilh, Be" uniqKey="Dutilh B">BE Dutilh</name>
</author>
<author>
<name sortKey="Ghaffaari, A" uniqKey="Ghaffaari A">A Ghaffaari</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Paten, B" uniqKey="Paten B">B Paten</name>
</author>
<author>
<name sortKey="Novak, Am" uniqKey="Novak A">AM Novak</name>
</author>
<author>
<name sortKey="Eizenga, Jm" uniqKey="Eizenga J">JM Eizenga</name>
</author>
<author>
<name sortKey="Garrison, E" uniqKey="Garrison E">E Garrison</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Baaijens, Ja" uniqKey="Baaijens J">JA Baaijens</name>
</author>
<author>
<name sortKey="El Aabidine, Az" uniqKey="El Aabidine A">AZ El Aabidine</name>
</author>
<author>
<name sortKey="Rivals, E" uniqKey="Rivals E">E Rivals</name>
</author>
<author>
<name sortKey="Schonhuth, A" uniqKey="Schonhuth A">A Schönhuth</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Dunne, Wm" uniqKey="Dunne W">WM Dunne</name>
</author>
<author>
<name sortKey="Jaillard, M" uniqKey="Jaillard M">M Jaillard</name>
</author>
<author>
<name sortKey="Rochas, O" uniqKey="Rochas O">O Rochas</name>
</author>
<author>
<name sortKey="Van Belkum, A" uniqKey="Van Belkum A">A Van Belkum</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kos, Vn" uniqKey="Kos V">VN Kos</name>
</author>
<author>
<name sortKey="Deraspe, M" uniqKey="Deraspe M">M Déraspe</name>
</author>
<author>
<name sortKey="Mclaughlin, Re" uniqKey="Mclaughlin R">RE McLaughlin</name>
</author>
<author>
<name sortKey="Whiteaker, Jd" uniqKey="Whiteaker J">JD Whiteaker</name>
</author>
<author>
<name sortKey="Roy, Ph" uniqKey="Roy P">PH Roy</name>
</author>
<author>
<name sortKey="Alm, Ra" uniqKey="Alm R">RA Alm</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bradley, P" uniqKey="Bradley P">P Bradley</name>
</author>
<author>
<name sortKey="Gordon, Nc" uniqKey="Gordon N">NC Gordon</name>
</author>
<author>
<name sortKey="Walker, Tm" uniqKey="Walker T">TM Walker</name>
</author>
<author>
<name sortKey="Dunn, L" uniqKey="Dunn L">L Dunn</name>
</author>
<author>
<name sortKey="Heys, S" uniqKey="Heys S">S Heys</name>
</author>
<author>
<name sortKey="Huang, B" uniqKey="Huang B">B Huang</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Moradigaravand, D" uniqKey="Moradigaravand D">D Moradigaravand</name>
</author>
<author>
<name sortKey="Palm, M" uniqKey="Palm M">M Palm</name>
</author>
<author>
<name sortKey="Farewell, A" uniqKey="Farewell A">A Farewell</name>
</author>
<author>
<name sortKey="Mustonen, V" uniqKey="Mustonen V">V Mustonen</name>
</author>
<author>
<name sortKey="Warringer, J" uniqKey="Warringer J">J Warringer</name>
</author>
<author>
<name sortKey="Parts, L" uniqKey="Parts L">L Parts</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Butler, J" uniqKey="Butler J">J Butler</name>
</author>
<author>
<name sortKey="Maccallum, I" uniqKey="Maccallum I">I MacCallum</name>
</author>
<author>
<name sortKey="Kleber, M" uniqKey="Kleber M">M Kleber</name>
</author>
<author>
<name sortKey="Shlyakhter, Ia" uniqKey="Shlyakhter I">IA Shlyakhter</name>
</author>
<author>
<name sortKey="Belmonte, Mk" uniqKey="Belmonte M">MK Belmonte</name>
</author>
<author>
<name sortKey="Lander, Es" uniqKey="Lander E">ES Lander</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zerbino, D" uniqKey="Zerbino D">D Zerbino</name>
</author>
<author>
<name sortKey="Birney, E" uniqKey="Birney E">E Birney</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Chikhi, R" uniqKey="Chikhi R">R Chikhi</name>
</author>
<author>
<name sortKey="Limasset, A" uniqKey="Limasset A">A Limasset</name>
</author>
<author>
<name sortKey="Medvedev, P" uniqKey="Medvedev P">P Medvedev</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Drezen, E" uniqKey="Drezen E">E Drezen</name>
</author>
<author>
<name sortKey="Rizk, G" uniqKey="Rizk G">G Rizk</name>
</author>
<author>
<name sortKey="Chikhi, R" uniqKey="Chikhi R">R Chikhi</name>
</author>
<author>
<name sortKey="Deltel, C" uniqKey="Deltel C">C Deltel</name>
</author>
<author>
<name sortKey="Lemaitre, C" uniqKey="Lemaitre C">C Lemaitre</name>
</author>
<author>
<name sortKey="Peterlongo, P" uniqKey="Peterlongo P">P Peterlongo</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Limasset, A" uniqKey="Limasset A">A Limasset</name>
</author>
<author>
<name sortKey="Rizk, G" uniqKey="Rizk G">G Rizk</name>
</author>
<author>
<name sortKey="Chikhi, R" uniqKey="Chikhi R">R Chikhi</name>
</author>
<author>
<name sortKey="Peterlongo, P" uniqKey="Peterlongo P">P Peterlongo</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Balding, Dj" uniqKey="Balding D">DJ Balding</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zhou, X" uniqKey="Zhou X">X Zhou</name>
</author>
<author>
<name sortKey="Stephens, M" uniqKey="Stephens M">M Stephens</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Widmer, C" uniqKey="Widmer C">C Widmer</name>
</author>
<author>
<name sortKey="Lippert, C" uniqKey="Lippert C">C Lippert</name>
</author>
<author>
<name sortKey="Weissbrod, O" uniqKey="Weissbrod O">O Weissbrod</name>
</author>
<author>
<name sortKey="Fusi, N" uniqKey="Fusi N">N Fusi</name>
</author>
<author>
<name sortKey="Kadie, C" uniqKey="Kadie C">C Kadie</name>
</author>
<author>
<name sortKey="Davidson, R" uniqKey="Davidson R">R Davidson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Falush, D" uniqKey="Falush D">D Falush</name>
</author>
<author>
<name sortKey="Bowden, R" uniqKey="Bowden R">R Bowden</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Collins, C" uniqKey="Collins C">C Collins</name>
</author>
<author>
<name sortKey="Didelot, X" uniqKey="Didelot X">X Didelot</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zhou, X" uniqKey="Zhou X">X Zhou</name>
</author>
<author>
<name sortKey="Stephens, M" uniqKey="Stephens M">M Stephens</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Benjamini, Y" uniqKey="Benjamini Y">Y Benjamini</name>
</author>
<author>
<name sortKey="Hochberg, Y" uniqKey="Hochberg Y">Y Hochberg</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Camacho, C" uniqKey="Camacho C">C Camacho</name>
</author>
<author>
<name sortKey="Coulouris, G" uniqKey="Coulouris G">G Coulouris</name>
</author>
<author>
<name sortKey="Avagyan, V" uniqKey="Avagyan V">V Avagyan</name>
</author>
<author>
<name sortKey="Ma, N" uniqKey="Ma N">N Ma</name>
</author>
<author>
<name sortKey="Papadopoulos, J" uniqKey="Papadopoulos J">J Papadopoulos</name>
</author>
<author>
<name sortKey="Bealer, K" uniqKey="Bealer K">K Bealer</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zankari, E" uniqKey="Zankari E">E Zankari</name>
</author>
<author>
<name sortKey="Hasman, H" uniqKey="Hasman H">H Hasman</name>
</author>
<author>
<name sortKey="Cosentino, S" uniqKey="Cosentino S">S Cosentino</name>
</author>
<author>
<name sortKey="Vestergaard, M" uniqKey="Vestergaard M">M Vestergaard</name>
</author>
<author>
<name sortKey="Rasmussen, S" uniqKey="Rasmussen S">S Rasmussen</name>
</author>
<author>
<name sortKey="Lund, O" uniqKey="Lund O">O Lund</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Lakin, Sm" uniqKey="Lakin S">SM Lakin</name>
</author>
<author>
<name sortKey="Dean, C" uniqKey="Dean C">C Dean</name>
</author>
<author>
<name sortKey="Noyes, Nr" uniqKey="Noyes N">NR Noyes</name>
</author>
<author>
<name sortKey="Dettenwanger, A" uniqKey="Dettenwanger A">A Dettenwanger</name>
</author>
<author>
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</author>
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</author>
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</author>
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</author>
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</author>
<author>
<name sortKey="Huck, G" uniqKey="Huck G">G Huck</name>
</author>
<author>
<name sortKey="Dong, Y" uniqKey="Dong Y">Y Dong</name>
</author>
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<name sortKey="Sumer, O" uniqKey="Sumer O">O Sumer</name>
</author>
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</author>
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</author>
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</author>
<author>
<name sortKey="Lafave, Mc" uniqKey="Lafave M">MC LaFave</name>
</author>
<author>
<name sortKey="Akella, S" uniqKey="Akella S">S Akella</name>
</author>
<author>
<name sortKey="Veyrieras, Jb" uniqKey="Veyrieras J">JB Veyrieras</name>
</author>
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</author>
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</author>
<author>
<name sortKey="Trauner, A" uniqKey="Trauner A">A Trauner</name>
</author>
<author>
<name sortKey="Gagneux, S" uniqKey="Gagneux S">S Gagneux</name>
</author>
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</author>
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</author>
<author>
<name sortKey="Assaf, R" uniqKey="Assaf R">R Assaf</name>
</author>
<author>
<name sortKey="Boisvert, S" uniqKey="Boisvert S">S Boisvert</name>
</author>
<author>
<name sortKey="Brettin, T" uniqKey="Brettin T">T Brettin</name>
</author>
<author>
<name sortKey="Bun, C" uniqKey="Bun C">C Bun</name>
</author>
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<name sortKey="Mlynarczyk, A" uniqKey="Mlynarczyk A">A Mlynarczyk</name>
</author>
<author>
<name sortKey="Mlynarczyk, G" uniqKey="Mlynarczyk G">G Mlynarczyk</name>
</author>
<author>
<name sortKey="Jeljaszewicz, J" uniqKey="Jeljaszewicz J">J Jeljaszewicz</name>
</author>
</analytic>
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<author>
<name sortKey="Liu, Yy" uniqKey="Liu Y">YY Liu</name>
</author>
<author>
<name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name>
</author>
<author>
<name sortKey="Walsh, Tr" uniqKey="Walsh T">TR Walsh</name>
</author>
<author>
<name sortKey="Yi, Lx" uniqKey="Yi L">LX Yi</name>
</author>
<author>
<name sortKey="Zhang, R" uniqKey="Zhang R">R Zhang</name>
</author>
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</author>
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</author>
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</author>
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</author>
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</author>
<author>
<name sortKey="Pot, B" uniqKey="Pot B">B Pot</name>
</author>
<author>
<name sortKey="Cornelis, P" uniqKey="Cornelis P">P Cornelis</name>
</author>
<author>
<name sortKey="Zizi, M" uniqKey="Zizi M">M Zizi</name>
</author>
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</author>
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<name sortKey="Coll, F" uniqKey="Coll F">F Coll</name>
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</author>
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</author>
<author>
<name sortKey="Guerra Assuncao, Ja" uniqKey="Guerra Assuncao J">JA Guerra-Assunção</name>
</author>
<author>
<name sortKey="Warry, A" uniqKey="Warry A">A Warry</name>
</author>
<author>
<name sortKey="Hill Cawthorne, G" uniqKey="Hill Cawthorne G">G Hill-Cawthorne</name>
</author>
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<name sortKey="Ondov, Bd" uniqKey="Ondov B">BD Ondov</name>
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</author>
<author>
<name sortKey="Melsted, P" uniqKey="Melsted P">P Melsted</name>
</author>
<author>
<name sortKey="Mallonee, Ab" uniqKey="Mallonee A">AB Mallonee</name>
</author>
<author>
<name sortKey="Bergman, Nh" uniqKey="Bergman N">NH Bergman</name>
</author>
<author>
<name sortKey="Koren, S" uniqKey="Koren S">S Koren</name>
</author>
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<author>
<name sortKey="Marcais, G" uniqKey="Marcais G">G Marçais</name>
</author>
<author>
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</author>
</analytic>
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</author>
<author>
<name sortKey="Vandervalk, Bp" uniqKey="Vandervalk B">BP Vandervalk</name>
</author>
<author>
<name sortKey="Mohamadi, H" uniqKey="Mohamadi H">H Mohamadi</name>
</author>
<author>
<name sortKey="Chu, J" uniqKey="Chu J">J Chu</name>
</author>
<author>
<name sortKey="Yeo, S" uniqKey="Yeo S">S Yeo</name>
</author>
<author>
<name sortKey="Hammond, Sa" uniqKey="Hammond S">SA Hammond</name>
</author>
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<contrib contrib-type="author" equal-contrib="yes">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-7010-1921</contrib-id>
<name>
<surname>Jaillard</surname>
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<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-8976-2762</contrib-id>
<name>
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</name>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-2459-9831</contrib-id>
<name>
<surname>Tournoud</surname>
<given-names>Maud</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mahé</surname>
<given-names>Pierre</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>van Belkum</surname>
<given-names>Alex</given-names>
</name>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lacroix</surname>
<given-names>Vincent</given-names>
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<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-7826-2719</contrib-id>
<name>
<surname>Jacob</surname>
<given-names>Laurent</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff001">
<label>1</label>
<addr-line>bioMérieux, Marcy l’Étoile, France</addr-line>
</aff>
<aff id="aff002">
<label>2</label>
<addr-line>Univ Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR5558 F-69622 Villeurbanne, France</addr-line>
</aff>
<aff id="aff003">
<label>3</label>
<addr-line>EPI ERABLE - Inria Grenoble, Rhône-Alpes, France</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Didelot</surname>
<given-names>Xavier</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Imperial College London, UNITED KINGDOM</addr-line>
</aff>
<author-notes>
<fn fn-type="COI-statement" id="coi001">
<p>I have read the journal’s policy and the authors of this manuscript have the following competing interests: MJ, MT, PM and AvB are employees of bioMérieux, a company that develops and sells diagnostic tests in the field of infectious diseases. However, the study was designed and executed in an open manner and the presented method as well as all data generated have been deposited in the public domain, also resulting in the current publication.</p>
</fn>
<corresp id="cor001">* E-mail:
<email>magali.dancette@biomerieux.com</email>
</corresp>
</author-notes>
<pub-date pub-type="collection">
<month>11</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="epub">
<day>12</day>
<month>11</month>
<year>2018</year>
</pub-date>
<volume>14</volume>
<issue>11</issue>
<elocation-id>e1007758</elocation-id>
<history>
<date date-type="received">
<day>4</day>
<month>6</month>
<year>2018</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>10</month>
<year>2018</year>
</date>
</history>
<permissions>
<copyright-statement>© 2018 Jaillard et al</copyright-statement>
<copyright-year>2018</copyright-year>
<copyright-holder>Jaillard et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<license-p>This is an open access article distributed under the terms of the
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="pgen.1007758.pdf"></self-uri>
<abstract>
<p>Genome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or detailed assessment of marker effect. Recently, alignment-free methods based on k-mer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are sometimes hard to interpret. Here we introduce DBGWAS, an extended k-mer-based GWAS method producing interpretable genetic variants associated with distinct phenotypes. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is alignment-free and only requires a set of contigs and phenotypes. In particular, it does not require prior annotation or reference genomes. It produces subgraphs representing phenotype-associated genetic variants such as local polymorphisms and mobile genetic elements (MGE). It offers a graphical framework which helps interpret GWAS results. Importantly it is also computationally efficient—experiments took one hour and a half on average. We validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in
<italic>Mycobacterium tuberculosis</italic>
, and genes acquired by horizontal transfer in
<italic>Staphylococcus aureus</italic>
and
<italic>Pseudomonas aeruginosa</italic>
—along with their MGE context. It also enabled us to formulate new hypotheses involving genetic variants not yet described in the antibiotic resistance literature. An open-source tool implementing DBGWAS is available at
<ext-link ext-link-type="uri" xlink:href="https://gitlab.com/leoisl/dbgwas">https://gitlab.com/leoisl/dbgwas</ext-link>
.</p>
</abstract>
<abstract abstract-type="summary">
<title>Author summary</title>
<p>Genome-wide association studies (GWAS) help explore the genetic bases of phenotype variation in a population. Our objective is to make GWAS amenable to bacterial genomes. These genomes can be too different to be aligned against a reference, even within a single species, making the description of their genetic variation challenging. We test the association between the phenotype and the presence in the genomes of DNA subsequences of length
<italic>k</italic>
– the so-called k-mers. These k-mers provide a versatile descriptor, allowing to capture genetic variants ranging from local polymorphisms to insertions of large mobile genetic elements. Unfortunately, they are also redundant and difficult to interpret. We rely on the compacted De Bruijn graph (cDBG), which represents the overlaps between k-mers. A single cDBG is built across all genomes, automatically removing the redundancy among consecutive k-mers, and allowing for a visualisation of the genomic context of the significant ones. We provide a computationally efficient and user-friendly implementation, enabling non-bioinformaticians to carry out GWAS on thousands of isolates in a few hours. This approach was effective in catching the dynamics of mobile genetic elements in
<italic>Staphylococcus aureus</italic>
and
<italic>Pseudomonas aeruginosa</italic>
genomes, and retrieved known local polymorphisms in
<italic>Mycobacterium tuberculosis</italic>
genomes.</p>
</abstract>
<funding-group>
<award-group id="award001">
<funding-source>
<institution-wrap>
<institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001665</institution-id>
<institution>Agence Nationale de la Recherche</institution>
</institution-wrap>
</funding-source>
<award-id>ANR-12-BS02-0008</award-id>
<principal-award-recipient>
<name>
<surname>Lacroix</surname>
<given-names>Vincent</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002">
<funding-source>
<institution-wrap>
<institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001665</institution-id>
<institution>Agence Nationale de la Recherche</institution>
</institution-wrap>
</funding-source>
<award-id>ANR-16-CE23-0001</award-id>
<principal-award-recipient>
<name>
<surname>Lacroix</surname>
<given-names>Vincent</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award003">
<funding-source>
<institution-wrap>
<institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001665</institution-id>
<institution>Agence Nationale de la Recherche</institution>
</institution-wrap>
</funding-source>
<award-id>ANR-14-CE23-0003-01</award-id>
<principal-award-recipient>
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-7826-2719</contrib-id>
<name>
<surname>Jacob</surname>
<given-names>Laurent</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award004">
<funding-source>
<institution-wrap>
<institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001665</institution-id>
<institution>Agence Nationale de la Recherche</institution>
</institution-wrap>
</funding-source>
<award-id>ANR-17-CE23-0011-01</award-id>
<principal-award-recipient>
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-7826-2719</contrib-id>
<name>
<surname>Jacob</surname>
<given-names>Laurent</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award005">
<funding-source>
<institution-wrap>
<institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100003593</institution-id>
<institution>Conselho Nacional de Desenvolvimento Científico e Tecnológico</institution>
</institution-wrap>
</funding-source>
<award-id>203362/2014-4</award-id>
<principal-award-recipient>
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-8976-2762</contrib-id>
<name>
<surname>Lima</surname>
<given-names>Leandro</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>MJ, MT, PM and AvB are employees of bioMérieux. LL is funded by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico – CNPq, Brazil, under the Science Without Borders scholarship grant process number 203362/2014-4. VL is funded by the Agence Nationale de la Recherche ANR-12-BS02-0008 (Colib’read) and ANR-16-CE23-0001 (ASTER). LJ is funded by the Agence Nationale de la Recherche ANR-14-CE23-0003-01 (MACARON) and ANR-17-CE23-0011-01 (FAST-BIG). This work was performed using the computing facilities of the CC LBBE/PRABI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<fig-count count="6"></fig-count>
<table-count count="4"></table-count>
<page-count count="28"></page-count>
</counts>
<custom-meta-group>
<custom-meta>
<meta-name>PLOS Publication Stage</meta-name>
<meta-value>vor-update-to-uncorrected-proof</meta-value>
</custom-meta>
<custom-meta>
<meta-name>Publication Update</meta-name>
<meta-value>2018-11-26</meta-value>
</custom-meta>
<custom-meta id="data-availability">
<meta-name>Data Availability</meta-name>
<meta-value>We put online all the GWAS results generated by our method which are discussed in the manuscript (
<ext-link ext-link-type="uri" xlink:href="http://pbil.univ-lyon1.fr/datasets/DBGWAS_support/">http://pbil.univ-lyon1.fr/datasets/DBGWAS_support/</ext-link>
). The proposed method is available on gitlab:
<ext-link ext-link-type="uri" xlink:href="https://gitlab.com/leoisl/dbgwas/">https://gitlab.com/leoisl/dbgwas/</ext-link>
.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes>
<title>Data Availability</title>
<p>We put online all the GWAS results generated by our method which are discussed in the manuscript (
<ext-link ext-link-type="uri" xlink:href="http://pbil.univ-lyon1.fr/datasets/DBGWAS_support/">http://pbil.univ-lyon1.fr/datasets/DBGWAS_support/</ext-link>
). The proposed method is available on gitlab:
<ext-link ext-link-type="uri" xlink:href="https://gitlab.com/leoisl/dbgwas/">https://gitlab.com/leoisl/dbgwas/</ext-link>
.</p>
</notes>
</front>
</pmc>
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