%0 Journal Article %A Mitchell J Sullivan %A Deena R Altman %A Kieran I Chacko %A Brianne Ciferri %A Elizabeth Webster %A Theodore R. Pak %A Gintaras Deikus %A Martha Lewis-Sandari %A Zenab Khan %A Colleen Beckford %A Angela Rendo %A Flora Samaroo %A Robert Sebra %A Ramona Karam-Howlin %A Tanis Dingle %A Camille Hamula %A Ali Bashir %A Eric Schadt %A Gopi Patel %A Frances Wallach %A Andrew Kasarskis %A Kathleen Gibbs %A Harm van Bakel %T Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events %D 2019 %R 10.1101/522078 %J bioRxiv %P 522078 %X Whole-genome sequencing (WGS) is widely used for studying MRSA evolution but it is not yet a common component of infection prevention practices. We established a continuous genome screening program of all first episode single-patient MRSA blood infections at a major urban hospital. A survey of 132 finished-quality MRSA genomes between 2014-2015 revealed a mixed background of hospital-(USA100/500/800) and community-associated (USA300-NA) lineages, and substantial variation among lineages outside core genomic regions. Megabase-scale inversions caused by homologous recombinations between endogenous prophages were common, particularly among USA100 isolates (28%). We further characterized three transmissions between six adults, and an extended clonal outbreak of USA100 among 3 adults and 18 infants in a neonatal intensive care unit (NICU) lasting 7 months. An analysis of all genetic changes among 23 additional complete isolate genomes obtained during the outbreak provided full spatiotemporal resolution of its origins and progression, which was likely precipitated by ventilator sharing and characterized by several sub-transmissions. The outbreak clone carried distinct mutations in genes with roles in metabolism, drug resistance and persistence. This included a DNA recognition domain recombination in the hsdS gene of a Type-I restriction-modification system that altered DNA methylation patterns. RNA-Seq profiling in vitro showed that the (epi)genetic changes attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation in the outbreak clone, which may have contributed to its spread. Our findings demonstrate the value of a program that provides routine complete genome screening as part of standard infection prevention practices. %U https://www.biorxiv.org/content/biorxiv/early/2019/01/17/522078.full.pdf