In this study, we assemble a detailed functional genomics dataset for a representative collection of 36 S. pneumoniae strains by performing: (1) single-molecule real-time sequencing (SMRT-seq), (2) RNA-seq and (3) Tn-seq. We show that the species contains 206 universally essential genes (always present and essential), 186 core strain-specific essential genes (always present but not always essential) and 128 accessory essential genes (essential when present). We show that these different essential-gene types have different (phenotypic) characteristics; we also use 'forced-evolution' experiments to determine how probable it is that a 'solution' exists for an essential gene to become non-essential. We show that while it is hard for a universal gene to lose its essentiality, core strain-specific and accessory essentials can switch to non-essentiality due to genetic background changes. Importantly, we show that differential essential genes remain important antimicrobial drug target candidates, as their deletion almost always has a fitness cost in vitro and in vivo.
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