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EN | DE

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

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

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

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

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

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

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

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

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

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-

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