RT Journal Article SR Electronic T1 The pathobiology of Mycobacterium abscessus revealed through phenogenomic analysis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.10.18.464689 DO 10.1101/2021.10.18.464689 A1 Lucas Boeck A1 Sophie Burbaud A1 Marcin Skwark A1 Will H. Pearson A1 Jasper Sangen A1 Aaron Weimann A1 Isobel Everall A1 Josephine M Bryant A1 Sony Malhotra A1 Bridget P. Bannerman A1 Katrin Kierdorf A1 Tom L. Blundell A1 Marc S. Dionne A1 Julian Parkhill A1 R. Andres Floto YR 2021 UL http://biorxiv.org/content/early/2021/10/18/2021.10.18.464689.abstract AB The medical and scientific response to emerging pathogens is often severely hampered by ignorance of the genetic determinants of virulence, drug resistance, and clinical outcomes that could be used to identify therapeutic drug targets and forecast patient trajectories 1–5. Taking the newly emergent multidrug-resistant bacteria Mycobacterium abscessus as an example 6, we show that combining high dimensional phenotyping with whole genome sequencing in a phenogenomic analysis can rapidly reveal actionable systems-level insights into bacterial pathobiology. Using in vitro and in vivo phenotyping, we discovered three distinct clusters of isolates, each associated with a different clinical outcome. We combined genome-wide association studies (GWAS) with proteome-wide computational structural modelling 7 to define likely causal variants, and employed direct coupling analysis (DCA) 8 to identify co-evolving, and therefore potentially epistatic, gene networks. We then used in vivo CRISPR-based silencing to validate our findings, defining a novel secretion system controlling virulence in M. abscessus, and illustrating how phenogenomics can reveal critical pathways within emerging pathogenic bacteria.Competing Interest StatementThe authors have declared no competing interest.