Heterozygosity: An expanding role in proteomics

The human genome sequence provides the framework for understanding the biol ogy of human cell function. The next step is to intensify the investigation of protein function in the context of complex biological systems. Cellular functions are carried out by molecular complexes acting in concert rather than by single molecules or single reactions. Parallels have been drawn bet ween scale-free nonbiologic networks and functionally interconnected metabo lic pathways in the cell. Modeling of metabolic networks, in which function al modules or subnetworks represent individual related pathways, will lead to the prediction of protein function in the larger context of a complex sy stem. Depending on the robustness of these metabolic networks, single-gene defects alone or in combination with other gene defects and the environment have the potential for invoking a spectrum of alterations in the integrity of a given network. The overall purpose of this review is to highlight the importance of simple heterozygosity for one pathogenic mutation or combina torial heterozygosity for two or more mutations within or between individua l genes in altering the stability of metabolic networks. Several forms of h eterozygosity are considered, e.g., intra- and interallelic heterozygosity and double heterozygosity. The concepts of synergistic heterozygosity, loss of heterozygosity, and mitochondrial DNA heteroplasmy also are discussed i n relation to the quantitative effects of coexisting mutations on the pheno typic expression of disease. (C) 2001 Academic Press.