148 CATALYZING INQUIRY
5.4.2.3 A Computational Model to Determine the Effects of SNPs in
Human Pathophysiology of Red Blood Cells
The completion of the Human Genome Project has led to the construction of single nucleotide
polymorphism (SNP) maps. Single nucleotide polymorphisms are common DNA sequence variations
among individuals. A result of the construction of SNP maps is to determine the effects of SNPs on the
development of disease(s) since sequence variations can lead to altered biological function or disease.
Currently, it is difficult to determine the causal relationship between the variations in sequence,
SNPs, and the physiological function. One way to analyze this relationship is to create computational
models or simulations of biological processes. Since erythrocyte (red blood cell) metabolism has been
studied extensively over the years and many SNPs have been characterized, Jamshidi et al. used this
information to build their computational models.^60
Two important metabolic enzymes, glucose-6-phosphate dehydrogenase (G6PD) and pyruvate ki-
nase (PK), were studied for alterations in their kinetic properties in an in silico model to calculate the
overall effect of SNPs on red blood cell function. Defects in these enzymes cause hemolytic anemia.
FIGURE 5.7 Bifurcation diagram for the full cell-cycle control network.... [T]he full diagram is not a simple sum of the
bifurcation diagrams of its modules. In particular, oscillations around the M state are greatly modified in the composite
control system. Superimposed on the bifurcation diagram is a “cell-cycle orbit” (line on the right with arrows): from
the time courses in Figure 5.6, we plot size on the abscissa and cdc2–cdc13 activity on the ordinate for representative
times between birth and division. Notice that, at small cell size, all three modules support stable steady states. Notice
how the cell-cycle orbit follows the attractors of the control system. SOURCE: J.J. Tyson, K. Chen and B. Novak,
“Network Dynamics and Cell Physiology,” Nature Reviews Molecular Cell Biology 2(12):908-916, 2001. Figure and caption,
reproduced with permission from Nature Reviews Molecular Cell Biology. Copyright 2001 Macmillan Magazines Ltd.
(^60) N. Jamshidi, S.J. Wiback, and B.O. Palsson, “In Silico Model-driven Assessment of the Effects of Single Nucleotide Polymor-
phisms (SNPs) on Human Red Blood Cell Metabolism,” Genome Research 12(11):1687-1692, 2002.