Characterization of heterogeneity in populations

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Characterization of bacterial strains

Two projects focus on developing workflows to assess and interpret multi-omics data and use it to characterize strain variation in different E. coli strains, including different species, strain-specific variants from adaptive laboratory evolution, and biofuel-producing strains.

1. Engineered E. coli strains for biofuel production

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Summary:
“The confluence of two accelerating fields—synthetic biology/pathway engineering and systems biology—presents exciting opportunities for the discovery of novel, economic solutions to industrial challenges. Conceptually, these “two worlds” have commonly operated under the pretense of distinct technical and theoretical frameworks, despite common engineering origins. Whereas systems biologists largely define a host organism by the underlying metabolic pathways and biological components, synthetic biologists commonly focus on the design of parts or modules according to biochemical and biological principles. Brunk et al describe a workflow that integrates these strengths, or forces these two worlds to collide, to facilitate high-throughout generation, analysis, and improvement of engineered microorganisms.” – Cell Systems preview article

Highlights:

  • 8 biofuel-producing E. coli strains assessed with comprehensive multi-omics data
  • Three-stage workflow incorporates computational, systems, and synthetic biology
  • Interactions between synthetic and endogenous metabolic pathways explored
  • Genome-scale modeling identifies a knockout that increases isopentenol productivity
  • Reference Publications:

2. Proteome comparison of entire species / strain-specific variants

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Highlights:

  • Comprehensive proteome comparisons of 55 E. coli strains assessed with GEM-PRO
  • Certain amino acid differences point to strategies for adaptation in specific environments
  • Significant amino acid differences at the surfaces of proteins link to changes at the interfaces of protein-protein interactions
  • Conserved amino acids in specific strain variants identify causal mutations underlying different phenotypes in K12 strains adapted to low pH

Reference Publications:

  • Brunk, E; Mih, N; McCloskey, D; Zhang, Z; Monk, J; Palsson, BO.  Variation in proteome composition illustrates strategies of adaptations to strain-specific environmental niches in preparation

Characterization of Human Heterogeneity

We are developing a multi-scale framework that integrates a systems biology model of metabolism for the human erythrocyte with protein structure and molecular modeling tools, such as molecular dynamics and binding free energy calculations. By integrating these complementary, yet classically separate methods, we can understand how single nucleotide polymorphisms (SNPs) affect native metabolism and drug responses.

Highlights:

  • Exploration of mechanistic underpinnings of human metabolism and its dysfunction in metabolic diseases
  • Bioinformatics-based workflows for data mining of drug and pharmacogenomics data
  • Evaluation of structural and binding properties of wild-type proteins and SNP variants
  • Understanding how SNPs change the course of a drug therapy and/or affect native metabolism

Reference Publications:

  •  Mih, N*; Brunk, E*; Bordbar, A; Palsson, BO. The Effect of Single Nucleotide Polymorphisms on Native Metabolite and Drug Responses in Human Erythrocyte Metabolism (2016)  accepted in Plos Comp Bio
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