Neutral Theory, Disease Mutations, and Personal Exomes

摘要: Genetic differences between species and within populations are two sides of the same coin under neutral theory molecular evolution. This posits that a vast majority evolutionary substitutions, which appear as species, (nearly) neutral, is, these substitutions permitted without significantly adverse impact on species' survival. We refer to them evolutionarily permissible (ePerm) variation. Evolutionary permissibility any possible variant can be inferred from multispecies sequence alignments by applying sophisticated statistical methods tree species. Here, we explore amino acid variants associated with genetic diseases those observed in personal exomes. Consistent predictions theory, disease rarely ePerm, much more biochemically radical, found predominantly at conserved positions than their non-disease counterparts. Only 10% mutations but rise become two-thirds all human lineage (a 6-fold enrichment). In contrast, only minority exome seemingly counterintuitive pattern results combination mutational processes are, fact, broadly consistent theory. Evolutionarily forbidden outnumber detrimental individual exomes may play an underappreciated role protecting against disease. discuss observations conclude long-term history illuminate functional biomedical properties variation present