The quantitative metabolome is shaped by abiotic constraints

Funding Information: We thank Jared Broddrick’s for his valuable comments on the manuscript. We would like to thank Sharon Grubner and Jonathan Hsu. This work was funded by the Novo Nordisk Foundation (Grant Number NNF10CC1016517), the National Institutes of Health (Grant Number GM057089), and the Institute for Systems Biology’s Translational Research Fellows Program (J.T.Y.). Publisher Copyright: © 2021, The Author(s).Living systems formed and evolved under constraints that govern their interactions with the inorganic world. These interactions are definable using basic physico-chemical principles. Here, we formulate a comprehensive set of ten governing abiotic constraints that define possible quantitative metabolomes. We apply these constraints to a metabolic network of Escherichia coli that represents 90% of its metabolome. We show that the quantitative metabolomes allowed by the abiotic constraints are consistent with metabolomic and isotope-labeling data. We find that: (i) abiotic constraints drive the evolution of high-affinity phosphate transporters; (ii) Charge-, hydrogen- and magnesium-related constraints underlie transcriptional regulatory responses to osmotic stress; and (iii) hydrogen-ion and charge imbalance underlie transcriptional regulatory responses to acid stress. Thus, quantifying the constraints that the inorganic world imposes on living systems provides insights into their key characteristics, helps understand the outcomes of evolutionary adaptation, and should be considered as a fundamental part of theoretical biology and for understanding the constraints on evolution.Peer reviewe

Comparative pangenomics : analysis of 12 microbial pathogen pangenomes reveals conserved global structures of genetic and functional diversity

Publisher Copyright:© 2021, The Author(s). This research was supported by a grant from the National Institute of Allergy and Infectious Diseases (AI124316, awarded to JMM and BOP, https://www.niaid.nih.gov/). This research was also supported by a grant from the National Institutes of Health (T32GM8806, awarded to JCH, https://www.nih.gov/).Background: With the exponential growth of publicly available genome sequences, pangenome analyses have provided increasingly complete pictures of genetic diversity for many microbial species. However, relatively few studies have scaled beyond single pangenomes to compare global genetic diversity both within and across different species. We present here several methods for “comparative pangenomics” that can be used to contextualize multi-pangenome scale genetic diversity with gene function for multiple species at multiple resolutions: pangenome shape, genes, sequence variants, and positions within variants. Results: Applied to 12,676 genomes across 12 microbial pathogenic species, we observed several shared resolution-specific patterns of genetic diversity: First, pangenome openness is associated with species’ phylogenetic placement. Second, relationships between gene function and frequency are conserved across species, with core genomes enriched for metabolic and ribosomal genes and accessory genomes for trafficking, secretion, and defense-associated genes. Third, genes in core genomes with the highest sequence diversity are functionally diverse. Finally, certain protein domains are consistently mutation enriched across multiple species, especially among aminoacyl-tRNA synthetases where the extent of a domain’s mutation enrichment is strongly function-dependent. Conclusions: These results illustrate the value of each resolution at uncovering distinct aspects in the relationship between genetic and functional diversity across multiple species. With the continued growth of the number of sequenced genomes, these methods will reveal additional universal patterns of genetic diversity at the pangenome scale.Peer reviewe