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

Group Leader

Postdoc

PhD Student

PhD Student

PhD Student

Master Student

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.

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 Research, 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

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)

Microbial Genomics, 4 (11): 00022DOI: 10.1099/mgen.0.000229

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)

Environmental Microbiology, 20 (11): 4079-4090DOI: 10.1111/1462-2920.14458

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)

Molecular Cell, 70 (5): 971-982DOI: 10.1016/j.molcel.2018.04.017

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)

Scientific Reports, 8 (1): 9868DOI: 10.1038/s41598-018-28199-y

Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica

Wheeler N, Gardner P, Barquist L (2018)

PLoS Genetics, 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)

Proceedings Of The National Academy Of Sciences Of The United States Of America, 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)

Infection And Immunity, 85 (9): 00419-17DOI: 10.1128/IAI.00419-17

Resolving host-pathogen interactions by dual RNA-seq

Westermann A, Barquist L, Vogel J (2017)

PLoS Pathogens, 13 (2): 10060

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)

The EMBO Journal, 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)

Nature Genetics, 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)

Current Protocols In Bioinformatics, 54: 1-12DOI: 10.1002/cpbi.4

Molecular phenotyping of infection-associated small non-coding RNAs

Barquist L, Westermann A, Vogel J (2016)

Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences, 371 (1707): 20160DOI: 10.1098/rstb.2016.0081

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)

Annual Review Of Genetics, 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)

Proceedings Of The National Academy Of Sciences Of The United States Of America, 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 Neglected Tropical Diseases, 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 Computational Biology, 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)

Proceedings Of The National Academy Of Sciences Of The United States Of America, 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 Research, 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 Research, 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 Genetics, 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)

Journal Of Bacteriology, 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 Pathogens, 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 Research, 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 Research, 36 (Web Server issue): 65-DOI: 10.1093/nar/gkn283

Jun Prof Lars Barquist

Integrative Informatics for Infection Biology

Our research and approach

Team members