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Jun Prof Lars Barquist

Integrative Informatics for Infection Biology

The research group led by Lars Barquist works on the development of new statistical, bioinformatic, and visualization approaches to functional genomics data. They bring together sequencing data and new computational technologies to provide new insights into bacterial pathogenesis and advance RNA-based therapeutics.

Our research and approach

The development of high-throughput technologies in infection biology allows thousands of genetic loci to be interrogated simultaneously in a single experiment. This has resulted in an accumulation of gene expression, fitness, and regulatory interaction data. The bottleneck in advancing our understanding of pathogens now lies in moving from hypothesis-free screening through data integration to hypothesis generation.

Lars Barquist’s group works on the development of new statistical, bioinformatic, and visualization approaches. Their work applies tools such as machine learning and Bayesian statistics to provide insight into bacterial pathogens, with the ultimate aim of overcoming the current bottleneck in the interpretation of complex post-genomic data.

Together with other research groups at the HIRI, the group has worked on the application of a variety of technologies, including CLIP seq, Dual RNA seq, CRISPRi screens, transposon mutagenesis and meta-transcriptomics. Their overarching goal is to bring together sequencing data and new computational technologies to advance our understanding of bacterial pathogenesis and the development of RNA-based therapeutics.

Team members

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

2021

RNA landscape of the emerging cancer-associated microbe Fusobacterium nucleatum

Ponath F, Tawk C, Zhu Y, Barquist L, Faber F, Vogel J (2021)

Nature Microbiology (Online ahead print)

Noncanonical crRNAs derived from host transcripts enable multiplexable RNA detection by Cas9

Jiao C, Sharma S, Dugar G, Peeck NL, Bischler T, Wimmer F, Yu Y, Barquist L, Schoen C, Kurzai O, Sharma CM, Beisel CL (2021)

Science 372 (6545): 941-948

Global RNA profiles show target selectivity and physiological effects of peptide-delivered antisense antibiotics

Popella L, Jung J, Popova K, Ðurica-Mitic S, Barquist L, Vogel J (2021)

Nucleic Acids Research 49 (8): 4705-4724

An RNA-centric global view of Clostridioides difficile reveals broad activity of Hfq in a clinically important gram-positive bacterium

Fuchs M, Lamm-Schmidt V, Sulzer J, Ponath F, Jenniches L, Kirk JA, Fagan RP, Barquist L, Vogel J, Faber F (2021)

Proceedings of the National Academy of Sciences of the United States of America 118 (25)

Functional analysis of colonization factor antigen I positive enterotoxigenic Escherichia coli identifies genes implicated in survival in water and host colonization

Abd El Ghany M, Barquist L, Clare S, Brandt C, Mayho M, Joffre E, Sjöling Å, Turner AK, Klena JD, Kingsley RA, …, Dougan G, Pickard D (2021)

Microbial Genomics 7 (6)

Global identification of RsmA/N binding sites in Pseudomonas aeruginosa by in vivo UV CLIP-seq

Chihara K, Barquist L, Takasugi K, Noda N, Tsuneda S (2021)

RNA Biology (Online ahead of print)

2020

A high-resolution transcriptome map identifies small RNA regulation of metabolism in the gut microbe Bacteroides thetaiotaomicron

Ryan D, Jenniches L, Reichardt S, Barquist L, Westermann AJ (2020)

Nature Communications 11: 3557

Dual RNA-seq of Orientia tsutsugamushi informs on host-pathogen interactions for this neglected intracellular human pathogen

Mika-Gospodorz B, Giengkam S, Westermann AJ, Wongsantichon J, Kion-Crosby W, Chuenklin S, Wang LC, Sunyakumthorn P, Sobota RM, Subbian S, …, Barquist L, Salje J (2020)

Nature Communications 11: 3363

An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria

Elliott AG, Huang JX, Neve S, Zuegg J, Edwards IA, Cain AK, Boinett CJ, Barquist L, Lundberg CV, Steen J, …, Strandh M, Cooper MA (2020)

Nature Communications 11: 3184

A decade of advances in transposon-insertion sequencing

Cain AK, Barquist L, Goodman AL, Paulsen IT, Parkhill J, van Opijnen T (2020)

Nature Reviews Genetics 21 (9): 526-540

The minimal meningococcal ProQ protein has an intrinsic capacity for structure-based global RNA recognition

Bauriedl S, Gerovac M, Heidrich N, Bischler T, Barquist L, Vogel J, Schoen C (2020)

Nature Communications 11: 2823

An RNA-centric global view of Clostridioides difficile reveals broad activity of Hfq in a clinically important Gram-positive bacterium

Fuchs M, Lamm-Schmidt V, Ponath F, Jenniches L, Barquist L, Vogel J, Faber F (2020)

Preprint

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Venturini E, Svensson SL, Maaß S, Gelhausen R, Eggenhofer F, Li L, Cain AK, Parkhill J, Becher D, Backofen R, …, Westermann AJ, Vogel J (2020)

microLife 1 (1): 597

Single-Nucleotide RNA Maps for the Two Major Nosocomial Pathogens Enterococcus faecalis and Enterococcus faecium

Michaux C, Hansen EE, Jenniches L, Gerovac M, Barquist L, Vogel J (2020)

Frontiers in Cellular and Infection Microbiology 10: 60032

Whole genome sequencing of Thametopoea pityocampa revealed putative pesticide targets

Shahraki A, Yu Y, Gul ZM, Liang C, Iyison NB (2020)

Genomics 112 (6): 4203-4207

Global discovery of bacterial RNA-binding proteins by RNase-sensitive gradient profiles reports a new FinO domain protein

Gerovac M, El Mouali Y, Kuper J, Kisker C, Barquist L, Vogel J (2020)

RNA 26 (10): 1448-1463

Plugging Small RNAs into the Network

Barquist L (2020)

mSystems 5 (3): 00422-20

2019

Rapid transcriptional responses to serum exposure are associated with sensitivity and resistance to antibody-mediated complement killing in invasive Salmonella Typhimurium ST313

Ondari EM, Klemm EJ, Msefula CL, El Ghany MA, Heath JN, Pickard DJ, Barquist L, Dougan G, Kingsley RA, MacLennan CA (2019)

Wellcome Open Research 4: 74

Transcriptional noise and exaptation as sources for bacterial sRNAs

Jose BR, Gardner PP, Barquist L (2019)

Biochemical Society Transactions 47 (2): 527-539

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)

Molecular Cell 70 (5): 971-982

A global genomic approach uncovers novel components for twitching motility-mediated biofilm expansion in Pseudomonas aeruginosa

Nolan LM, Whitchurch CB, Barquist L, Katrib M, Boinett CJ, Mayho M, Goulding D, Charles IG, Filloux A, Parkhill J, Cain AK (2018)

Microbial Genomics 4 (11): 00022

Functional analysis of Salmonella Typhi adaptation to survival in water

Kingsley RA, Langridge G, Smith SE, Makendi C, Fookes M, Wileman TM, El Ghany MA, Keith Turner A, Dyson ZA, Sridhar S, …, Barquist L, Dougan G (2018)

Environmental Microbiology 20 (11): 4079-4090

Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin

Cain AK, Boinett CJ, Barquist L, Dordel J, Fookes M, Mayho M, Ellington MJ, Goulding D, Pickard D, Wick RR, …, Parkhill J, Thomson NR (2018)

Scientific Reports 8 (1): 9868

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

Wheeler NE, Gardner PP, Barquist L (2018)

PLOS Genetics 14 (5): 10073

2017

The primary transcriptome of Neisseria meningitidis and its interaction with the RNA chaperone Hfq

Heidrich N, Bauriedl S, Barquist L, Li L, Schoen C, Vogel J (2017)

Nucleic Acids Research 45 (10): 6147-6167

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 AJ, Gunn JS, Vogel J (2017)

Proceedings of the National Academy of Sciences of the United States of America 114 (26): 6824-6829

Role of sapA and yfgA in Susceptibility to Antibody-Mediated Complement-Dependent Killing and Virulence of Salmonella enterica Serovar Typhimurium

Ondari EM, Heath JN, Klemm EJ, Langridge G, Barquist L, Goulding DA, Clare S, Dougan G, Kingsley RA, MacLennan CA (2017)

Infection and Immunity 85 (9): 00419-17

Resolving host-pathogen interactions by dual RNA-seq

Westermann AJ, Barquist L, Vogel J (2017)

PLOS Pathogens 13 (2): 10060

2016

Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings

Feasey NA, Hadfield J, Keddy KH, Dallman TJ, Jacobs J, Deng X, Wigley P, Barquist L, Langridge GC, Feltwell T, …, Gordon MA, Thomson NR (2016)

Nature Genetics 48 (10): 1211-1217

Dual RNA-seq unveils noncoding RNA functions in host-pathogen interactions

Westermann AJ, Forstner KU, Amman F, Barquist L, Chao Y, Schulte LN, Muller L, Reinhardt R, Stadler PF, Vogel J (2016)

Nature 529 (7587): 496-501

Global RNA recognition patterns of post-transcriptional regulators Hfq and CsrA revealed by UV crosslinking in vivo

Holmqvist E, Wright PR, Li L, Bischler T, Barquist L, Reinhardt R, Backofen R, Vogel J (2016)

The EMBO Journal 35 (9): 991-1011

The TraDIS toolkit: sequencing and analysis for dense transposon mutant libraries

Barquist L, Mayho M, Cummins C, Cain AK, Boinett CJ, Page AJ, Langridge GC, Quail MA, Keane JA, Parkhill J (2016)

Bioinformatics 32 (7): 1109-11

Studying RNA Homology and Conservation with Infernal: From Single Sequences to RNA Families

Barquist L, Burge SW, Gardner PP (2016)

Current Protocols in Bioinformatics 54: 1-12

Molecular phenotyping of infection-associated small non-coding RNAs

Barquist L, Westermann AJ, Vogel J (2016)

Philosophical Transactions of the Royal Society of London B: Biological Sciences 371 (1707): 20160

The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium

Read HM, Mills G, Johnson S, Tsai P, Dalton J, Barquist L, Print CG, Patrick WM, Wiles S (2016)

PeerJ 4: 2130

A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes

Wheeler NE, Barquist L, Kingsley RA, Gardner PP (2016)

Bioinformatics 32 (23): 3566-3574

2015

Accelerating Discovery and Functional Analysis of Small RNAs with New Technologies

Barquist L, Vogel J (2015)

Annual Review of Genetics 49: 367-94

High-throughput analysis of gene essentiality and sporulation in Clostridium difficile

Dembek M, Barquist L, Boinett CJ, Cain AK, Mayho M, Lawley TD, Fairweather NF, Fagan RP (2015)

mBio 6 (2): 02383

Patterns of genome evolution that have accompanied host adaptation in Salmonella

Langridge GC, Fookes M, Connor TR, Feltwell T, Feasey N, Parsons BN, Seth-Smith HM, Barquist L, Stedman A, Humphrey T, …, Dougan G, Thomson NR (2015)

Proceedings of the National Academy of Sciences of the United States of America 112 (3): 863-8

Signatures of adaptation in human invasive Salmonella Typhimurium ST313 populations from sub-Saharan Africa

Okoro CK, Barquist L, Connor TR, Harris SR, Clare S, Stevens MP, Arends MJ, Hale C, Kane L, Pickard DJ, …, Dougan G, Kingsley RA (2015)

PLOS Neglected Tropical Diseases 9 (3): 00036

2014

Functional genomics reveals that Clostridium difficile Spo0A coordinates sporulation, virulence and metabolism

Pettit LJ, Browne HP, Yu L, Smits WK, Fagan RP, Barquist L, Martin MJ, Goulding D, Duncan SH, Flint HJ, …, Choudhary JS, Lawley TD (2014)

BMC Genomics 15: 160

Robust identification of noncoding RNA from transcriptomes requires phylogenetically-informed sampling

Lindgreen S, Umu SU, Lai AS, Eldai H, Liu W, McGimpsey S, Wheeler NE, Biggs PJ, Thomson NR, Barquist L, Poole AM, Gardner PP (2014)

PLOS Computational Biology 10 (10): 10039

Parallel independent evolution of pathogenicity within the genus Yersinia

Reuter S, Connor TR, Barquist L, Walker D, Feltwell T, Harris SR, Fookes M, Hall ME, Petty NK, Fuchs TM, …, McNally A, Thomson NR (2014)

Proceedings of the National Academy of Sciences of the United States of America 111 (18): 6768-73

An introduction to RNA databases

Hoeppner MP, Barquist L, Gardner PP (2014)

In: RNA Sequence, Structure, and Function: Computational and Bioinformatic Methods (eds Gorodkin J, Ruzzo W), Methods Mol Biol 1097: 107-23

2013

Rfam 11.0: 10 years of RNA families

Burge SW, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki EP, Eddy SR, Gardner PP, Bateman A (2013)

Nucleic Acids Research 41 (Database issue): 226-32

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 NM, Reid AJ, Ramsay JP, Williamson NR, Croucher NJ, Gatto L, Hester SS, Goulding D, Barquist L, Lilley KS, …, Dougan G, Salmond GP (2013)

BMC Genomics 14: 822

A comparison of dense transposon insertion libraries in the Salmonella serovars Typhi and Typhimurium

Barquist L, Langridge GC, Turner DJ, Phan M, Turner AK, Bateman A, Parkhill J, Wain J, Gardner PP (2013)

Nucleic Acids Research 41 (8): 4549-64

Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection

Croucher NJ, Mitchell AM, Gould KA, Inverarity D, Barquist L, Feltwell T, Fookes MC, Harris SR, Dordel J, Salter SJ, …, Mitchell TJ, Bentley SD (2013)

PLOS Genetics 9 (10): 10038

The agr locus regulates virulence and colonization genes in Clostridium difficile 027

Martin MJ, Clare S, Goulding D, Faulds-Pain A, Barquist L, Browne HP, Pettit LJ, Dougan G, Lawley TD, Wren BW (2013)

Journal of Bacteriology 195 (16): 3672-81

Approaches to querying bacterial genomes with transposon-insertion sequencing

Barquist L, Boinett CJ, Cain AK (2013)

RNA Biology 10 (7): 1161-9

Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica serovar Typhimurium pathovar

Kingsley RA, Kay S, Connor T, Barquist L, Sait L, Holt KE, Sivaraman K, Wileman TM, Goulding D, Clare S, …, Parkhill J, Dougan G (2013)

mBio 4 (5): 00565-13

Characterization of the yehUT two-component regulatory system of Salmonella enterica Serovar Typhi and Typhimurium

Wong VK, Pickard DJ, Barquist L, Sivaraman K, Page AJ, Hart PJ, Arends MJ, Holt KE, Kane L, Mottram LF, …, Kingsley RA, Dougan G (2013)

PLOS One 8 (12): 84567

2012

A high-resolution view of genome-wide pneumococcal transformation

Croucher NJ, Harris SR, Barquist L, Parkhill J, Bentley SD (2012)

PLOS Pathogens 8 (6): 10027

HandAlign: Bayesian multiple sequence alignment, phylogeny and ancestral reconstruction

Westesson O, Barquist L, Holmes I (2012)

Bioinformatics 28 (8): 1170-1

2011

RNIE: genome-wide prediction of bacterial intrinsic terminators

Gardner PP, Barquist L, Bateman A, Nawrocki EP, Weinberg Z (2011)

Nucleic Acids Research 39 (14): 5845-52

2009

Evolutionary modeling and prediction of non-coding RNAs in Drosophila

Bradley RK, Uzilov AV, Skinner ME, Bendana YR, Barquist L, Holmes I (2009)

PLOS One 4 (8): 6478

2008

xREI: a phylo-grammar visualization webserver

Barquist L, Holmes I (2008)

Nucleic Acids Research 36 (Web Server issue): 65-