Genomes of a major nosocomial pathogen Enterococcus faecium are shaped by adaptive evolution of the chromosome and plasmidome

Enterococcus faecium is a gut commensal of many mammals but is also recognized as a major nosocomial human pathogen, as it is listed on the WHO global priority list of multi-drug resistant organisms. Previous research has suggested that nosocomial strains have multiple zoonotic origins and are only distantly related to those involved in human commensal colonization. Here we present the first comprehensive population-wide joint genomic analysis of hospital, commensal and animal isolates using both short- and long-read sequencing techniques. This enabled us to investigate the population plasmidome, core genome variation and genome architecture in detail, using a combination of machine learning, population genomics and genome-wide co-evolution analysis. We observed a high level of genome plasticity with large-scale inversions and heterogeneous chromosome sizes, collectively painting a high-resolution picture of the adaptive landscape of E. faecium , and identified plasmids as the main indicator for host-specificity. Given the increasing availability of long-read sequencing technologies, our approach could be widely applied to other human and animal pathogen populations to unravel fine-scale mechanisms of their evolution.