Transcript Nutrigenomics/pharmacogenomics Lactose intolerance: C/T(-13910) lactase persistence/non functions in vitro as a cis element 14kbp upstream enhancing the lactase promoter http://www.genecards.org/cgi-bin/carddisp.pl?gene=LCT.

Nutrigenomics/pharmacogenomics
Lactose intolerance:
C/T(-13910) lactase
persistence/non functions
in vitro as a cis element
14kbp upstream
enhancing the lactase
promoter
http://www.genecards.org/cgi-bin/carddisp.pl?gene=LCT
Nutrigenomics/pharmacogenomics
Thiopurine methyltransferase (TPMT) metabolizes 6mercaptopurine 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).
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. 2007 Feb
6;104(6):1777-82.
Joyce AR, Palsson BO. Toward whole cell modeling and simulation:
comprehensive functional genomics through the constraint-based
approach. Prog Drug Res. 2007;64:265, 267-309. Review.
Herring, et al. Comparative genome sequencing of Escherichia coli
allows observation of bacterial evolution on a laboratory timescale.
Nat Genet. 2006 38:1406-12.
Desai RP, Nielsen LK, Papoutsakis ET. Stoichiometric modeling of
Clostridium acetobutylicum fermentations with non-linear
constraints. J Biotechnol. 1999 71:191-205.
Human metabolic Network (Recon 1)
Duarte et al. reconstruction of the
human metabolic network based on
genomic and bibliomic data. PNAS
2007 104:1777-82.
E.coli: 1200 ORFs
http://gcrg.ucsd.edu/organisms
Flux
Data
Predicted Fluxes
C009-limited
200
180
160
140
120
100
80
60
40
20
0
WT (LP)
9
10
1
2
6 17
1545
0
250
18
150
8
2
7
9
100
14
5
46
3
r=-0.06
p=6e-1
10
13
11
12
Predicted Fluxes
Predicted Fluxes
200
50
250
Dpyk (LP)
200
15
17
141311
312
r=0.91
p=8e-8
16
18
50
100
150
Experimental Fluxes
8
150
100
14
10
9 13
11
31 12
50
0
200
Dpyk (QP)
7
16
0
7
8
r=0.56
P=7e-3
16
15
62
5
4 18
17
1
-50
-50
0
50 100 150 200 250
Experimental Fluxes
-50
-50
0
50 100 150 200 250
Experimental Fluxes
Competitive growth data:
reproducibility
Correlation between two selection experiments
Badarinarayana, et al. Nature Biotech.19: 1060
Competitive growth data
On minimal media
negative
selection
FBA
LP
QP
MOMA
small
effect
C 2 p-values
Essential
Reduced growth
Non essential
142
46
299
80
24
119
62
22
180
-3
p = 4∙10
4x10
Essential
Reduced growth
Non essential
162
44
281
96
19
108
66
25
173
p = 10-5
Position effects
-3
1x10-5
Novel redundancies
Hypothesis: next optima are achieved by regulation of activities.
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.
2005 91(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. 2005 61(2):171-80
Andries K, et al. (J&J) A diarylquinoline drug active
on the ATP synthase of Mycobacterium tuberculosis.
Science. 2005 307:223-7.
Shendure et al. Accurate Multiplex Polony Sequencing of an
Evolved Bacterial Genome Science 2005 309:1728 (Select for
secretion & ‘altruism’).