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  1. Evaluation Summary:

    This study offers a comprehensive examination of Staphylococcus aureus evolution during infection. This manuscript will be of broad interest to readers in the field of microbiology and infectious disease. It provides a useful analysis of a comprehensive set of genetic signatures of bacterial adaptation. A combination of multiple layers of genome annotation and point mutation variant detection compellingly supports the correlation of infection outcomes with adaptation signatures in S. aureus.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The study by Giulieri and colleagues focuses on the detection of genetic loci that experience selection in S. aureus during the transition from colonization to infection. The authors assembled a large collection of S. aureus genomes from prior studies and systematically analyzed them for genetic variation and signatures of genome degradation. They found significant convergent evolution in genes linked to antibiotic response and pathogenesis. The result is a high-resolution picture of S. aureus adaptation during the transition from colonization to infection.

    The major strength of the paper is the large scale of the analysis and the inclusion of additional variants besides SNPs, which are frequently ignored because they can be hard to reliably detect and study. One additional strength is the use of "multilayered" annotation (i.e. including intergenic variants) to increase signals of convergent evolution. One weakness of the study is a lack of a classification of the variants detected in convergent loci. For example, which genes do the authors think are acquiring gain-of-function versus loss-of-function mutations? One other weakness is a lack of functional studies exploring some of the more novel signals detected (such as hypothetical proteins with "no data on S. aureus").

    In general, the results support the conclusions drawn by the authors, the likely impact of the work is quite high, and overall it is a useful example of how to perform systematic detection of pathogen loci under selection in vivo during infection.

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  3. Reviewer #2 (Public Review):

    This work provides a comprehensive within-host evolution analysis of all publicly available Staphylococcus aureus genome. The authors combined variant and chromosome structural variants detecting, internal variant annotation, gene and operon enrichment analysis, mutation co-occurence analysis and network analysis of adaptation signatures, to compile a comprehensive catalogue of bacterial genetic variation arising during host infection. This strategy enabled the detection of convergent adaptation patterns at an unprecedented resolution. Through study, they found evidence of a distinctive evolutionary pattern within the infecting populations compared to colonising bacteria. In addition to reported agr-mediated adaptation, they identified non-canonical genome-wide significant loci including sucA-sucB and stp1. The prevalence of adaptive changes increased with infection extent, emphasising the clinical significance of these signatures. These findings provide a high-resolution picture of the molecular changes when S. aureus transitions from colonisation to severe infection and may inform the correlation of infection outcomes with adaptation signatures.

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