Jun Prof Lars Barquist
Integrative Informatics for Infection Biology
We develop systems approaches to RNA and infection, using modern visualization, data science, and machine learning technologies to integrate large-scale functional genomics data.
Our research and approach
Recent years have seen accelerating development of high-throughput technologies in infection biology. Now, thousands of genetic loci can be simultaneously interrogated in a single experiment, providing an array of measurements of transcription, translation, regulatory interactions, and fitness effects. The bottleneck in advancing our understanding of pathogens now lies in moving from hypothesis-free screening through data integration to hypothesis generation. We develop new statistical, bioinformatic, and visualization approaches to overcome this bottleneck in the interpretation of complex post-genomic data.
Team members
Jun Prof Lars Barquist
Group Leader
Dr Laura Jenniches
Postdoc
Bozena Mika-Gospodorz
PhD Student
Shuba Varshini Alampalli
PhD Student
Yanying Yu
PhD Student
Publications
2019
Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313
Ondari E, Klemm E, Msefula C, El Ghany M, Heath J, Pickard D, Barquist L, Dougan G, Kingsley R, MacLennan C (2019)
Wellcome Open Res, 4: 74DOI: 10.12688/wellcomeopenres.15059.1
Transcriptional noise and exaptation as sources for bacterial sRNAs
Jose B, Gardner P, Barquist L (2019)
Biochemical Society transactions, 47 (2): 527-539DOI: 10.1042/BST20180171
2018
Global Maps of ProQ Binding In Vivo Reveal Target Recognition via RNA Structure and Stability Control at mRNA 3' Ends
Holmqvist E, Li L, Bischler T, Barquist L, Vogel J (2018)
Mol Cell, 70 (5): 971-982DOI: 10.1016/j.molcel.2018.04.017
A global genomic approach uncovers novel components for twitching motility-mediated biofilm expansion in Pseudomonas aeruginosa
Nolan L, Whitchurch C, Barquist L, Katrib M, Boinett C, Mayho M, Goulding D, Charles I, Filloux A, Parkhill J, Cain A (2018)
Microb Genom, 4 (11): 00022DOI: 10.1099/mgen.0.000229
Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin
Cain A, Boinett C, Barquist L, Dordel J, Fookes M, Mayho M, Ellington M, Goulding D, Pickard D, Wick R, …, Parkhill J, Thomson N (2018)
Sci Rep, 8 (1): 9868DOI: 10.1038/s41598-018-28199-y
Functional analysis of Salmonella Typhi adaptation to survival in water
Kingsley R, Langridge G, Smith S, Makendi C, Fookes M, Wileman T, El Ghany M, Keith Turner A, Dyson Z, Sridhar S, …, Barquist L, Dougan G (2018)
Environ Microbiol, 20 (11): 4079-4090DOI: 10.1111/1462-2920.14458
Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica
Wheeler N, Gardner P, Barquist L (2018)
Plos Genet, 14 (5): 10073DOI: 10.1371/journal.pgen.1007333
2017
RNA target profiles direct the discovery of virulence functions for the cold-shock proteins CspC and CspE
Michaux C, Holmqvist E, Vasicek E, Sharan M, Barquist L, Westermann A, Gunn J, Vogel J (2017)
Proc Natl Acad Sci U S A, 114 (26): 6824-6829DOI: 10.1073/pnas.1620772114
Role of sapA and yfgA in Susceptibility to Antibody-Mediated Complement-Dependent Killing and Virulence of Salmonella enterica Serovar Typhimurium
Ondari E, Heath J, Klemm E, Langridge G, Barquist L, Goulding D, Clare S, Dougan G, Kingsley R, MacLennan C (2017)
Infect Immun, 85 (9): 00419-17DOI: 10.1128/IAI.00419-17
2016
Global RNA recognition patterns of post-transcriptional regulators Hfq and CsrA revealed by UV crosslinking in vivo
Holmqvist E, Wright P, Li L, Bischler T, Barquist L, Reinhardt R, Backofen R, Vogel J (2016)
EMBO J, 35 (9): 991-1011DOI: 10.15252/embj.201593360
The TraDIS toolkit: sequencing and analysis for dense transposon mutant libraries
Barquist L, Mayho M, Cummins C, Cain A, Boinett C, Page A, Langridge G, Quail M, Keane J, Parkhill J (2016)
Bioinformatics, 32 (7): 1109-11DOI: 10.1093/bioinformatics/btw022
Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings
Feasey N, Hadfield J, Keddy K, Dallman T, Jacobs J, Deng X, Wigley P, Barquist L, Langridge G, Feltwell T, …, Gordon M, Thomson N (2016)
Nat Genet, 48 (10): 1211-1217DOI: 10.1038/ng.3644
Studying RNA Homology and Conservation with Infernal: From Single Sequences to RNA Families
Barquist L, Burge S, Gardner P (2016)
Curr Protoc Bioinformatics, 54: 1-12DOI: 10.1002/cpbi.4
The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium
Read H, Mills G, Johnson S, Tsai P, Dalton J, Barquist L, Print C, Patrick W, Wiles S (2016)
PeerJ, 4: 2130DOI: 10.7717/peerj.2130
A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes
Wheeler N, Barquist L, Kingsley R, Gardner P (2016)
Bioinformatics, 32 (23): 3566-3574DOI: 10.1093/bioinformatics/btw518
2015
High-throughput analysis of gene essentiality and sporulation in Clostridium difficile
Dembek M, Barquist L, Boinett C, Cain A, Mayho M, Lawley T, Fairweather N, Fagan R (2015)
MBio, 6 (2): 02383DOI: 10.1128/mBio.02383-14
Accelerating Discovery and Functional Analysis of Small RNAs with New Technologies
Barquist L, Vogel J (2015)
Annu Rev Genet, 49: 367-94DOI: 10.1146/annurev-genet-112414-054804
Patterns of genome evolution that have accompanied host adaptation in Salmonella
Langridge G, Fookes M, Connor T, Feltwell T, Feasey N, Parsons B, Seth-Smith H, Barquist L, Stedman A, Humphrey T, …, Dougan G, Thomson N (2015)
Proc Natl Acad Sci U S A, 112 (3): 863-8DOI: 10.1073/pnas.1416707112
Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa
Okoro C, Barquist L, Connor T, Harris S, Clare S, Stevens M, Arends M, Hale C, Kane L, Pickard D, …, Dougan G, Kingsley R (2015)
PLos Negl Trop Dis, 9 (3): 00036DOI: 10.1371/journal.pntd.0003611
2014
Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism
Pettit L, Browne H, Yu L, Smits W, Fagan R, Barquist L, Martin M, Goulding D, Duncan S, Flint H, …, Choudhary J, Lawley T (2014)
BMC Genomics, 15: 160DOI: 10.1186/1471-2164-15-160
Robust identification of noncoding RNA from transcriptomes requires phylogenetically-informed sampling
Lindgreen S, Umu S, Lai A, Eldai H, Liu W, McGimpsey S, Wheeler N, Biggs P, Thomson N, Barquist L, Poole A, Gardner P (2014)
PLos Comput Biol, 10 (10): 10039DOI: 10.1371/journal.pcbi.1003907
Parallel independent evolution of pathogenicity within the genus Yersinia
Reuter S, Connor T, Barquist L, Walker D, Feltwell T, Harris S, Fookes M, Hall M, Petty N, Fuchs T, …, McNally A, Thomson N (2014)
Proc Natl Acad Sci U S A, 111 (18): 6768-73DOI: 10.1073/pnas.1317161111
An introduction to RNA databases
Hoeppner M, Barquist L, Gardner P (2014)
In: RNA Sequence, Structure, and Function: Computational and Bioinformatic Methods (eds Gorodkin J, Ruzzo W), Methods Mol Biol, 1097: 107-23DOI: 10.1007/978-1-62703-709-9_6
2013
Rfam 11.0: 10 years of RNA families
Burge S, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki E, Eddy S, Gardner P, Bateman A (2013)
Nucleic Acids Res, 41 (Database issue): 226-32DOI: 10.1093/nar/gks1005
RNA-seq reveals the RNA binding proteins, Hfq and RsmA, play various roles in virulence, antibiotic production and genomic flux in Serratia sp. ATCC 39006
Wilf N, Reid A, Ramsay J, Williamson N, Croucher N, Gatto L, Hester S, Goulding D, Barquist L, Lilley K, …, Dougan G, Salmond G (2013)
BMC Genomics, 14: 822DOI: 10.1186/1471-2164-14-822
A comparison of dense transposon insertion libraries in the Salmonella serovars Typhi and Typhimurium
Barquist L, Langridge G, Turner D, Phan M, Turner A, Bateman A, Parkhill J, Wain J, Gardner P (2013)
Nucleic Acids Res, 41 (8): 4549-64DOI: 10.1093/nar/gkt148
Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection
Croucher N, Mitchell A, Gould K, Inverarity D, Barquist L, Feltwell T, Fookes M, Harris S, Dordel J, Salter S, …, Mitchell T, Bentley S (2013)
Plos Genet, 9 (10): 10038DOI: 10.1371/journal.pgen.1003868
The agr locus regulates virulence and colonization genes in Clostridium difficile 027
Martin M, Clare S, Goulding D, Faulds-Pain A, Barquist L, Browne H, Pettit L, Dougan G, Lawley T, Wren B (2013)
J Bacteriol, 195 (16): 3672-81DOI: 10.1128/JB.00473-13
Approaches to querying bacterial genomes with transposon-insertion sequencing
Barquist L, Boinett C, Cain A (2013)
RNA biology, 10 (7): 1161-9DOI: 10.4161/rna.24765
Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica serovar Typhimurium pathovar
Kingsley R, Kay S, Connor T, Barquist L, Sait L, Holt K, Sivaraman K, Wileman T, Goulding D, Clare S, …, Parkhill J, Dougan G (2013)
MBio, 4 (5): 00565-13DOI: 10.1128/mBio.00565-13
Characterization of the yehUT two-component regulatory system of Salmonella enterica Serovar Typhi and Typhimurium
Wong V, Pickard D, Barquist L, Sivaraman K, Page A, Hart P, Arends M, Holt K, Kane L, Mottram L, …, Kingsley R, Dougan G (2013)
Plos One, 8 (12): 84567DOI: 10.1371/journal.pone.0084567
2012
A high-resolution view of genome-wide pneumococcal transformation
Croucher N, Harris S, Barquist L, Parkhill J, Bentley S (2012)
Plos Pathog, 8 (6): 10027DOI: 10.1371/journal.ppat.1002745
HandAlign: Bayesian multiple sequence alignment, phylogeny and ancestral reconstruction
Westesson O, Barquist L, Holmes I (2012)
Bioinformatics, 28 (8): 1170-1DOI: 10.1093/bioinformatics/bts058
2011
RNIE: genome-wide prediction of bacterial intrinsic terminators
Gardner P, Barquist L, Bateman A, Nawrocki E, Weinberg Z (2011)
Nucleic Acids Res, 39 (14): 5845-52DOI: 10.1093/nar/gkr168
2009
Evolutionary modeling and prediction of non-coding RNAs in Drosophila
Bradley R, Uzilov A, Skinner M, Bendana Y, Barquist L, Holmes I (2009)
Plos One, 4 (8): 6478DOI: 10.1371/journal.pone.0006478
2008
xREI: a phylo-grammar visualization webserver
Barquist L, Holmes I (2008)
Nucleic Acids Res, 36 (Web Server issue): 65-DOI: 10.1093/nar/gkn283
Research projects
We analyse and integrate genomic and post-genomic data to provide insight into bacterial pathogenesis. We have been active in developing bioinformatics techniques to analyze and interpret the results of experiments using high-throughput sequencing, including transposon-insertion sequencing, CLIP-seq, and dual RNA-seq. We are actively developing new algorithms and statistical approaches to these kinds of data to provide insight into both host-microbe interactions and RNA-based regulation in bacterial pathogens.
We have also been active in applying machine learning tools to the evolution of bacterial pathogens using genome sequencing data. By dissecting the architecture of these machines, we have been able to extract new insights into how pathogens adapt to their hosts. We are currently investigating way to incorporate additional layers of information, such as gene expression information and mutations in non-coding RNA, into such models to provide a more comprehensive view of pathogen behavior.