Yeast metabolic innovations emerged via expanded metabolic network and gene positive selection

Hongzhong Lu, Feiran Li, Le Yuan, Iván Domenzain, Rosemary Yu, Hao Wang, Gang Li, Yu Chen, Boyang Ji, Eduard J. Kerkhoven, Jens Nielsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Yeasts are known to have versatile metabolic traits, while how these metabolic traits have evolved has not been elucidated systematically. We performed integrative evolution analysis to investigate how genomic evolution determines trait generation by reconstructing genome-scale metabolic models (GEMs) for 332 yeasts. These GEMs could comprehensively characterize trait diversity and predict enzyme functionality, thereby signifying that sequence-level evolution has shaped reaction networks towards new metabolic functions. Strikingly, using GEMs, we can mechanistically map different evolutionary events, e.g. horizontal gene transfer and gene duplication, onto relevant subpathways to explain metabolic plasticity. This demonstrates that gene family expansion and enzyme promiscuity are prominent mechanisms for metabolic trait gains, while GEM simulations reveal that additional factors, such as gene loss from distant pathways, contribute to trait losses. Furthermore, our analysis could pinpoint to specific genes and pathways that have been under positive selection and relevant for the formulation of complex metabolic traits, i.e. thermotolerance and the Crabtree effect. Our findings illustrate how multidimensional evolution in both metabolic network structure and individual enzymes drives phenotypic variations.
Original languageEnglish
Article numbere10427
JournalMolecular Systems Biology
Issue number10
Publication statusPublished - 2021


  • genome analysis
  • genome-scale metabolic models
  • metabolic innovation
  • systems biology


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