Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Lees, John A.; Ferwerda, Bart; Kremer, Philip H. C.; Wheeler, Nicole E.; Serón, Mercedes Valls; Croucher, Nicholas J.; Gladstone, Rebecca A.; Bootsma, Hester J.; Rots, Nynke Y.; Wijmega-Monsuur, Alienke J.; Sanders, Elisabeth A. M.; Trzciński, Krzysztof; Wyllie, Anne L.; Zwinderman, Aeilko H.; Berg, Leonard H. van den; Rheenen, Wouter van; Veldink, Jan H.; Harboe, Zitta Barrella; Lundbo, Lene Fogt; Groot, Lisette C. P. G. M. de; Schoor, Natasja M. van; Velde, Nathalie van der; Ängquist, Lars; Sørensen, Thorkild I A; Nøhr, Ellen A.; Mentzer, Alexander J.; Mills, Tara C.; Knight, Julian C.; Plessis, Mignon du; Nzenze, Susan; Weiser, Jeffrey N.; Parkhill, Julian; Madhi, Shabir А.; Benfield, Thomas; Gottberg, Anne von; Ende, Arie van der; Brouwer, Matthijs C.; Barrett, Jeffrey C.; Bentley, Stephen D.; Beek, Diederik van de

doi:10.1038/s41467-019-09976-3

Cited by 96 publications

(107 citation statements)

References 113 publications

(128 reference statements)

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“…using heritability estimates established the presence of a strong relation between S. aureus genetic variation and pyomyositis, with estimated heritability at 63%. In another GWAS of human and pathogen, Lees et al (2019) show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity while Pneumococcal genetic variation explains a large amount of invasive potential (70%), but had no effect on severity. Determining heritability before performing GWAS is important to ensure that a substantial amount of variation is actually as a result of genetic variation.…”

Section: Analytical Considerations and Pitfallsmentioning

confidence: 99%

Current Affairs of Microbial Genome-Wide Association Studies: Approaches, Bottlenecks and Analytical Pitfalls

et al. 2020

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Microbial genome-wide association studies (mGWAS) are a new and exciting research field that is adapting human GWAS methods to understand how variations in microbial genomes affect host or pathogen phenotypes, such as drug resistance, virulence, host specificity and prognosis. Several computational tools and methods have been developed or adapted from human GWAS to facilitate the discovery of novel mutations and structural variations that are associated with the phenotypes of interest. However, no comprehensive, end-to-end, user-friendly tool is currently available. The development of a broadly applicable pipeline presents a real opportunity among computational biologists. Here, (i) we review the prominent and promising tools, (ii) discuss analytical pitfalls and bottlenecks in mGWAS, (iii) provide insights into the selection of appropriate tools, (iv) highlight the gaps that still need to be filled and how users and developers can work together to overcome these bottlenecks. Use of mGWAS research can inform drug repositioning decisions as well as accelerate the discovery and development of more effective vaccines and antimicrobials for pressing infectious diseases of global health significance, such as HIV, TB, influenza, and malaria.

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Section: Analytical Considerations and Pitfallsmentioning

confidence: 99%

Current Affairs of Microbial Genome-Wide Association Studies: Approaches, Bottlenecks and Analytical Pitfalls

et al. 2020

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“…Several bacterial GWAS have been reported for S. aureus (Alam et al 2014;Laabei et al 2014;Baines et al 2015;Young et al 2019) and other species (Howell et al 2014;Earle et al 2016;Coll et al 2017). These have largely addressed pathogenicity and virulence (Howell et al 2014;Laabei et al 2014;Lees et al 2016Lees et al , 2019, and antibiotic resistance (Alam et al 2014;Desjardins et al 2016;Earle et al 2016;Coll et al 2017). They have also highlighted the challenges of bacterial GWAS, including clonal populations with little recombination that lead to strong linkage disequilibrium, and variable gene content in the accessory genome (Earle et al 2016;Lees et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Contrasting approaches to genome-wide association studies impact the detection of resistance mechanisms in Staphylococcus aureus

Wheeler

Reuter

Chewapreecha

et al. 2019

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Rapid detection of antibiotic resistance using whole-genome sequencing (WGS) could improve clinical outcomes and limit the spread of resistance. For this to succeed, we need an accurate way of linking genotype to phenotype, that identifies new resistance mechanisms as they appear. To assess how close we are to this goal, we characterized antimicrobial resistance determinants in >4,000 Staphylococcus aureus genomes of isolates associated with bloodstream infection in the United Kingdom and Ireland. We sought to answer three questions: 1) how well did known resistance mechanisms explain phenotypic resistance in our collection, 2) how many previously identified resistance mechanisms appeared in our collection, and 3) how many of these were detectable using four contrasting genome-wide association study (GWAS) methods. Resistance prediction based on the detection of known resistance determinants was 98.8% accurate. We identified challenges in correcting for population structure, clustering orthologous genes, and identifying causal mechanisms in rare or common phenotypes, which reduced the recovery of known mechanisms. Limited sensitivity and specificity of these methods made prediction using GWAS-discovered hits alone less accurate than using literature-derived genetic determinants. However, GWAS methods identified novel mutations associated with resistance, including five mutations in rpsJ, which improved tetracycline resistance prediction for 28 isolates, and a T118I substitution in fusA which resulted in better fusidic acid resistance prediction for 5 isolates. Thus, GWAS approaches in conjunction with phenotypic testing data can support the development of comprehensive databases to enable real-time use of WGS for patient management.

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“…A study employing novel genome-wide association study (GWAS) and joint sequencing approaches identified pneumococcal genes important in meningitis that are involved in competence, metabolic pathways and bacteriocins. Host variation in Coiled-Coil Domain Containing 33 (CCDC33) and serine/threonine kinase 32C (STK32C) were associated with susceptibility to pneumococcal meningitis [108].…”

Section: New Frontiers In Pneumococcal "Omics" Genomics and Transmissionmentioning

confidence: 99%

State-of-the-art in the pneumococcal field: Proceedings of the 11th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-11)

2020

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The International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD) is the premier global scientific symposium dedicated to the exchange, advancement and dissemination of the latest research on the pneumococcus, one of the world's deadliest bacterial pathogens. Since the first ISPPD was held in 1998, substantial progress has been made to control pneumococcal disease, for instance, more than half of surviving infants (78.6 million) from 143 countries now have access to the life-saving pneumococcal conjugate vaccine (PCV). The 11th ISPPD (ISPPD-11) was held in Melbourne, Australia in April 2018 and the proceedings of the symposium are captured in this report. Twenty years on from the first ISPPD, there remain many challenges and unanswered questions such as the continued disparity in disease incidence in Indigenous populations, the slow roll-out of PCV in some regions such as Asia, the persisting burden of disease in adults, serotype replacement and diagnosis of pneumococcal pneumonia. ISPPD-11 also put the spotlight on cutting-edge science including metagenomic, transcriptomic, microscopy, medical imaging and mathematical modelling approaches. ISPPD-11 was highly diverse, bringing together 1184 delegates from 86 countries, representing various fields including academia, primary healthcare, pharmaceuticals, biotechnology, policymakers and public health.

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Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Cited by 96 publications

References 113 publications

Current Affairs of Microbial Genome-Wide Association Studies: Approaches, Bottlenecks and Analytical Pitfalls

Current Affairs of Microbial Genome-Wide Association Studies: Approaches, Bottlenecks and Analytical Pitfalls

Contrasting approaches to genome-wide association studies impact the detection of resistance mechanisms in Staphylococcus aureus

State-of-the-art in the pneumococcal field: Proceedings of the 11th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-11)

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