In Silico Model-Driven Assessment of the Effects of Single Nucleotide Polymorphisms (SNPs) on Human Red Blood Cell Metabolism

Abstract

The completion of the human genome project and the construction of single nucleotide polymorphism (SNP) maps have lead to significant efforts to find SNPs that can be linked to pathophysiology. In silico models of complete biochemical reaction networks relate a cell's individual reactions to the function of the entire network. Sequence variations can in turn be related to kinetic properties of individual enzymes, thus allowing an in silico model-driven assessment of the effects of defined SNPs on overall cellular functions. This process is applied to defined SNPs in two key enzymes of human red blood cell metabolism: glucose-6-phosphate dehydrogenase and pyruvate kinase. The results demonstrate the utility of in silico models in providing insight into differences between red cell function in patients with chronic and nonchronic anemia. In silico models of complex cellular processes are thus likely to aid in defining and understanding key SNPs in human pathophysiology.

Monte Carlo sampling can be used to determine the size and shape of the steady-state flux space

“…All the reactions fall well within the bounds of the polytope. In addition, 'lethal' stressed states calculated with the model (Jamshidi et al, 2002) also appear to fall within the bounds of the flux ranges despite the cell's in silico 'death' (results not shown). The fact that the cell cannot sustain these loads in silico yet do not appear to hit the applied constraints points to the fact that there are additional constraints placed on the cell that are not captured by the stoichiometry and reaction capacities.…”

“…If a constraint eliminates a large section of the solution space that does not contain the cell's operating point, than there will probably be no effect on the cell's function. However, if a constraint eliminates a section of the flux cone that contains the physiologic state then the cell's operating point will most probably be affected, as has been demonstrate with the in silico study of glucose-6-phosphate dehydrogenase and pyruvate kinase SNPs in (Jamshidi et al, 2002). 6.…”

Parallel analysis of mutant human glucose 6‐phosphate dehydrogenase in yeast using PCR colonies

“…(Brookes, 1999;Kruglyak, 1999). Finally, by using the type of information generated in this report in conjunction with metabolic models (Jamshidi et al, 2002), it will be possible to gain greater understanding of various metabolic disorders.…”

Dynamics of biological systems: role of systems biology in medical research

“…A model can represent a cellular system, where it is concerned with a mechanism or network within a single cell [41], or it can represent a whole organ or an organ system. For cellular systems, there are numerous examples: models of transport mechanisms and membrane permeability; metabolic models (e.g., red blood cell metabolism [42,43] or mitochondrial energy metabolism [44]), models of cell-signaling pathways (e.g., mitogen-activated protein kinase signaling [45,46], Wnt signaling [47], Jak-Stat signaling [48], caspase activation [49]); or cell-cycle models [50]. Additionally, there are already clinically relevant computer models of intra-and intercellular signaling [51].…”