1. Nutrigenomics/pharmacogenomics
Lactose intolerance:
C/T(-13910) lactase persistence/non functions in vitro as a cis element 14kbp upstream enhancing the lactase promoter

2. Nutrigenomics/pharmacogenomics
Thiopurine methyltransferase (TPMT) metabolizes 6-mercaptopurine and azathiopurine, two drugs used in a range of indications, from childhood leukemia to autoimmune diseases
CYP450 superfamily: CYP2D6 has over 75 known allelic variations, 30% of people in parts of East Africa have multiple copies of the gene, not be adequately treated with standard doses of drugs, e.g. codeine (activated by CYP2D6).

3. Further optimization readings
Duarte et al. reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci U S A Feb 6;104(6):
Joyce AR, Palsson BO. Toward whole cell modeling and simulation: comprehensive functional genomics through the constraint-based approach. Prog Drug Res. 2007;64:265, Review.
Herring, et al. Comparative genome sequencing of Escherichia coli allows observation of bacterial evolution on a laboratory timescale. Nat Genet :
Desai RP, Nielsen LK, Papoutsakis ET. Stoichiometric modeling of Clostridium acetobutylicum fermentations with non-linear constraints. J Biotechnol :

4. Human metabolic Network (Recon 1)
Duarte et al. reconstruction of the human metabolic network based on genomic and bibliomic data. PNAS :
E.coli: 1200 ORFs

5. Flux Data

6. C009-limited WT (LP) Dpyk (LP) Dpyk (QP) r=0.91 p=8e-8 r=0.56 r=-0.06
200
WT (LP)
180 7
160 8
140 9
120 10
Predicted Fluxes
100 14 13 11
r=0.91
p=8e-8 1 3 12 80 60 40 20 16 2 15 4 6 5 17 18 50
100
150
200
Experimental Fluxes
250
Dpyk (LP)
250
Dpyk (QP)
200 18
200 7
r=0.56
P=7e-3
150
r=-0.06
p=6e-1
150 8 7 2 8
Predicted Fluxes
Predicted Fluxes 10
100 9
100 9 13 11 10 14 3 1 12 14 13 11 50 3 12 50 4 5 6 16 16 2 15 15 17 6 5 4 18 17 1
-50
-50
-50 50
100
150
200
250
-50 50
100
150
200
250
Experimental Fluxes
Experimental Fluxes

7. Competitive growth data: reproducibility
Correlation between two selection experiments
Badarinarayana, et al. Nature Biotech.19: 1060

8. Competitive growth data
On minimal media
negative small
selection effect
C 2 p-values
4x10-3
1x10-5 LP QP
Novel redundancies
Position effects
Hypothesis: next optima are achieved by regulation of activities.

9. Intelligent Design & Metabolic Evolution
Fong SS, Burgard AP, Herring CD, Knight EM, Blattner FR, Maranas CD, Palsson BO. In silico design and adaptive evolution of Escherichia coli for production of lactic acid. Biotechnol Bioeng (5):643-8.
Rozen DE, Schneider D, Lenski RE Long-term experimental evolution in Escherichia coli. XIII. Phylogenetic history of a balanced polymorphism. J Mol Evol (2):171-80
Andries K, et al. (J&J) A diarylquinoline drug active
on the ATP synthase of Mycobacterium tuberculosis.
Science :223-7.
Shendure et al. Accurate Multiplex Polony Sequencing of an Evolved Bacterial Genome Science :1728 (Select for secretion & ‘altruism’).