Nutrigenomics/pharmacogenomics

1
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
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. 2007 Feb
6104(6)1777-82. Joyce AR, Palsson BO. Toward
whole cell modeling and simulation comprehensive
functional genomics through the constraint-based
approach. Prog Drug Res. 200764265, 267-309.
Review. Herring, et al. Comparative genome
sequencing of Escherichia coli allows observation
of bacterial evolution on a laboratory timescale.
Nat Genet. 2006 381406-12. Desai RP, Nielsen
LK, Papoutsakis ET. Stoichiometric modeling of
Clostridium acetobutylicum fermentations with
non-linear constraints. J Biotechnol. 1999
71191-205.
4
Human metabolic Network (Recon 1)
Duarte et al. reconstruction of the human
metabolic network based on genomic and bibliomic
data. PNAS 2007 1041777-82. E.coli 1200 ORFs
http//gcrg.ucsd.edu/organisms
5
Flux Data
6
C009-limited
200
WT (LP)
180
7
8
160
140
9
120
10
Predicted Fluxes
100
r0.91 p8e-8
11
13
14
12
3
1
80
60
40
16
20
2
5
6
4
15
17
18
0
0
50
100
150
200
Experimental Fluxes
250
250
Dpyk (LP)
Dpyk (QP)
200
200
18
7
r0.56 P7e-3
8
150
r-0.06 p6e-1
150
7
8
2
Predicted Fluxes
Predicted Fluxes
10
100
9
13
100
9
11
12
3
1
14
10
11
13
14
12
3
50
50
5
6
4
16
16
2
15
5
6
0
15
17
0
17
18
4
1
-50
-50
-50
0
50
100
150
200
250
-50
0
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.
  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. (JJ) A diarylquinoline drug
  active
• on the ATP synthase of Mycobacterium
  tuberculosis.
• Science. 2005 307223-7.
• Shendure et al. Accurate Multiplex Polony
  Sequencing of an Evolved Bacterial Genome
  Science 2005 3091728 (Select for secretion
  altruism).