Genotype, environment, and evolutionary mechanism of diseases

Large-scale genomic projects have unexpectedly challenged the current approach of focusing on genes in disease studies. As common gene mutations are difficult to identify for common/complex diseases, and the diagnostic distinction of gene profile between “normal” and “patient” becomes increasingly blurry, the power of gene-focused studies in medicine is actually decreasing. More attention is now being focused on gene–environment interaction. However, such a transition is still within the framework of using molecular descriptions of specific genes for understanding diseases, which is challenging in the clinic, where nonlinear relationships are dominant. In this article, we define diseases as genotype/environment-induced variants that are not compatible with a current environment. This explains (1) why the genotype is not simply the gene mutation profile, but comprised of multiple levels of genetic/nongenetic (including epigenetic) variations, as environmental dynamics require all sorts of system modifications; (2) why many disease conditions represent a trade-off of cellular adaptation, in addition to inherited or environment-induced bio-errors; and (3) why costly variants function as the “insurance policy” for adapting to the unpredictability of environments. This leads to the general mechanism of the majority of diseases: genotype–environment interaction generates variations, which are either essential for future crises or useful for current cellular function. Unfortunately, as a trade-off, these variants also contribute to diseases. This general mechanism can unify diverse specific molecular mechanisms, and suggests that the goal of eliminating all diseases is not only impossible, but also comes with the potential negative consequence of reducing the heterogeneity essential for human survival.