(498d) A Workflow for the Systems-Level Analysis, Design, and Engineering of Genomically Recoded Organisms
AIChE Annual Meeting
2022
2022 Annual Meeting
Food, Pharmaceutical & Bioengineering Division
Engineering bacteria for novel chemistry and interactions
Wednesday, November 16, 2022 - 1:24pm to 1:42pm
Here, we present a workflow for the rational analysis, design, and engineering of genomically recoded organisms. First, we have developed deep learning models connecting sequence-to-function of regulatory genetic features. Second, we have constructed extended genome-scale models for the integrative analysis of metabolism, expression, and regulation. These models can predict cellular fitness from recoded genome sequences and can integrate large and disparate omics data sets. Finally, we have defined optimization-based methods for the computational analysis of recoding mutations. With this workflow, we can predict at a systems-level the combinatorial effect of recoding mutations on fitness, and we identify sets of mutational bottlenecks constraining growth.
We are applying this workflow to identify fitness-decreasing mutations in genomically recoded strains of Escherichia coli. The models developed together with newly obtained RNA-seq data for these strains are helping characterize the metabolic function arising from synthetic genomes. In the future, this workflow will serve to design genomically recoded organisms with minimal growth reduction and will provide a better understanding of genotype-to-phenotype relationships at a cellular level.
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