Relating Mutant Genotype to Phenotype via Quantitative Behavior of the NADPH Redox Cycle in Human Erythrocytes

BACKGROUND: The NADPH redox cycle plays a key role in antioxidant protection of human erythrocytes. It consists of two enzymes: glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase. Over 160 G6PD variants have been characterized and associated with several distinct clinical manifestations. However, the mechanistic link between the genotype and the phenotype remains poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We address this issue through a novel framework (design space) that integrates information at the genetic, biochemical and clinical levels. Our analysis predicts three qualitatively-distinct phenotypic regions that can be ranked according to fitness. When G6PD variants are analyzed in design space, a correlation is revealed between the phenotypic region and the clinical manifestation: the best region with normal physiology, the second best region with a pathology, and the worst region with a potential lethality. We also show that Plasmodium falciparum, by induction of its own G6PD gene in G6PD-deficient erythrocytes, moves the operation of the cycle to a region of the design space that yields robust performance. CONCLUSIONS/SIGNIFICANCE: In conclusion, the design space for the NADPH redox cycle, which includes relationships among genotype, phenotype and environment, illuminates the function, design and fitness of the cycle, and its phenotypic regions correlate with the organism's clinical status.