Human genomic disease variants: A neutral evolutionary explanation

Abstract

Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease.

Evolution‐informed modeling improves outcome prediction for cancers

“…Such high molecular heterogeneity forms the foundation of diverse clinical outcomes and other cancer phenotypes, as well as makes hunting of cancer driver mutations very challenging (Heng, 2015). Our previous study showed that frequently observed cancer mutations are enriched at evolutionarily conserved positions (Dudley et al, 2012). Thus, evolutionary conservation estimated at the nucleotide level may help prioritize cancer driver mutations.…”

Understanding rare and common diseases in the context of human evolution

“…Most of the rare and common variants associated with susceptibility to disease in modern populations have emerged through neutral selection processes [184]. However, there is increasing evidence to suggest that, following changes in environmental variables or human lifestyle, alleles that were previously adaptive can become “maladaptive” and associated with disease risk [12, 13, 29, 30, 105].…”

Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association

“…However, distinguishing between neutral variants (i.e., those with little or no effect on phenotype) from variants associated with disease still remains a major challenge for both monogenic (Mendelian) and complex diseases . The current state‐of‐the‐art methods for diagnosing amino acid variants primarily employ evolutionary information obtained from multispecies sequence analysis in a variety of ways . While these methods have been used extensively, they often fail to correctly diagnose damaging variants at evolutionarily variable positions and neutral variants at highly conserved positions …”