The emergence of genotypic divergence and future precision medicine applications

Abstract

Genotypic divergence is a term adapted from population genetics and intimately linked to evolution. We use divergence here to emphasize the differences that set individuals apart in any cohort. The history of genetics is filled with descriptions of genotypic differences, but causal inference of interindividual biological variation has been scarce. We suggest that the practice of precision medicine requires a divergent approach, an approach dependent on the causal interpretation of previous convergent (and preliminary) knowledge in the field. This knowledge has relied on convergent descriptive syndromology (lumping), which has overemphasized a reductionistic gene determinism on the quest of seeking associations without causal understanding. Regulatory variants with small effect and somatic mutations are some of the modifying factors that lead to incomplete penetrance and intrafamilial variable expressivity often observed in apparently monogenic clinical disorders. A truly divergent approach to precision medicine requires splitting, that is, the consideration of different layers of genetic phenomena that interact causally in a nonlinear fashion. This chapter reviews convergences and divergences in genetics and genomics, aiming to discuss what can be causally understood to approximate the as-yet utopian lands of Precision Medicine for patients with neurodegenerative disorders.