Different alleles of the same gene vary in pleiotropy, often mediated through currency metabolite production

A major obstacle to the mapping of genotype-phenotype relationships is pleiotropy, the tendency of mutations to affect seemingly unrelated traits. Pleiotropy has major implications for evolution, development, ageing, and disease. Except for disease data, pleiotropy is almost exclusively estimated from full gene knockouts. However, most deleterious alleles segregating in natural populations do not fully abolish gene function, and the degree to which a polymorphism reduces protein function may influence the number of traits it affects. Utilizing genome-scale metabolic models for Escherichia coli and the baker9s yeast Saccharomyces cerevisiae, we show that most fitness-reducing full gene knockouts of metabolic genes have pleiotropic effects, i.e., they compromise the production of multiple biomass components. Alleles of the same gene with increasingly reduced enzyme function typically affect an increasing number of biomass components. This increasing pleiotropy is often mediated through effects on the generation of currency metabolites such as ATP or NADPH. We conclude that the physiological effects observed in full gene knockouts will in most cases not be representative for alleles with only partially reduced enzyme capacity or expression level.