Evolution
Notaro et al. (2000) showed that an evolutionary analysis is a key to understanding the biology of a housekeeping gene such as G6PD. From the alignment of the amino acid sequence of 52 G6PD species from 42 different organisms, they found a striking correlation between the amino acid replacements that cause G6PD deficiency in humans and the sequence conservation of G6PD. Two-thirds of such replacements were found in highly and moderately conserved (50 to 99%) amino acids; relatively few were located in fully conserved amino acids (where they might be lethal) or in poorly conserved amino acids (where presumably they simply would not cause G6PD deficiency). The findings were considered consistent with the notion that all human mutants have residual enzyme activity and that null mutations are lethal at some stage of development. Comparing the distribution of mutations in the 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.