Consequences of complexity within biological networks: robustness and health, or vulnerability and disease.

One promise of molecular genetics for many of us was that a detailed knowledge of mutant alleles would permit accurate prediction of prognosis and better selection of therapeutic strategies for Mendelian disorders (1). This presumed predictive promise was naive and was based on a reductionist view of genotype-phenotype correlations, i.e., that a refined and specific knowledge of a mutation’s impact on protein structure and function would permit extrapolation to the phenotype of the intact organism. The reality of molecular genetics, however, is that for many diseases only a subset of mutations reliably predicts phenotype. This lack of genotype-phenotype correlation for many Mendelian disorders shows us that the clinical phenotypes of “simple” Mendelian disorders are complex traits (1,2). In retrospect we should have recognized that an individual with a clinical disorder is not the product of the single gene that is disrupted, but that the genetic disruption is embedded within the context of that individual’s entire genome and environmental experience. Since