Expression level, cellular compartment and metabolic network position all influence the average selective constraint on mammalian enzymes

BACKGROUND: A gene's position in regulatory, protein interaction or metabolic networks can be predictive of the strength of purifying selection acting on it, but these relationships are neither universal nor invariably strong. Following work in bacteria, fungi and invertebrate animals, we explore the relationship between selective constraint and metabolic function in mammals. RESULTS: We measure the association between selective constraint, estimated by the ratio of nonsynonymous (K(a)) to synonymous (K(s)) substitutions, and several, primarily metabolic, measures of gene function. We find significant differences between the selective constraints acting on enzyme-coding genes from different cellular compartments, with the nucleus showing higher constraint than genes from either the cytoplasm or the mitochondria. Among metabolic genes, the centrality of an enzyme in the metabolic network is significantly correlated with K(a)/K(s). In contrast to yeasts, gene expression magnitude does not appear to be the primary predictor of selective constraint in these organisms. CONCLUSIONS: Our results imply that the relationship between selective constraint and enzyme centrality is complex: the strength of selective constraint acting on mammalian genes is quite variable and does not appear to exclusively follow patterns seen in other organisms.