Human mutations in glucose 6-phosphate dehydrogenase reflect evolutionary history

Glucose 6-phosphate dehydrogenase (G6PD) is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive bio synthetic reactions. Inherited G6PD deficiency is associated with either ep isodic hemolytic anemia (triggered by fava beans or other agents) or life-l ong hemolytic anemia. We show here that an evolutionary analysis is a key t o understanding the biology of a housekeeping gene, From the alignment of t he amino acid (aa) sequence of 52 glucose 6-phosphate dehydrogenase (G6PD) species from 42 different organisms, we found a striking correlation betwee n the aa replacements that cause G6PD deficiency in humans and the sequence conservation of G6PD: two-thirds of such replacements are in highly and mo derately conserved (50-99%) aa; relatively few are in fully conserved aa (w here they might be lethal) or in poorly conserved aa, where presumably they simply would not cause G6PD deficiency, This: is consistent with the notio n that all human mutants have residual enzyme activity and that null mutati ons are lethal at some stage of development, Comparing the distribution of mutations in a human housekeeping gene with evolutionary conservation is a useful tool for pinpointing amino acid residues important for the stability or the function of the corresponding protein. In view of the current explo sive increase in full genome sequencing projects, this tool will become rap idly available for numerous other genes.