Hypothetical novel simulations to explain the evolutionary survival of the hypo-reproductive extreme tail in the complex human diversity.

Hierarchical structures which lie hidden between human complex conditions and reproductivity cannot be simple, and trends of each population component does not necessarily pertain to evolutionary theories. As an illustration, the fitness of individuals with heritable extreme conditions can be low across continuing generations in observational data. Autism and schizophrenia are characterized by such evolutionary paradox of survival and hypo-reproductivity in the complex human diversity. Theoretical mechanisms for the observational fact were evaluated using a simple formula which was established to simulate stochastic epistasis-mediated phenotypic diversity. The survival of the hypo-reproductive extreme tail could be imitated just by the predominant presence of stochastic epistasis mechanism, suggesting that stochastic epistasis might be a genetic prerequisite for the evolutionary paradox. As supplemental cofactors of stochastic epistasis, a random link of the extreme tail to both un- and hyper-reproductivity and group assortative mating were shown to be effective for the paradox. Especially, the mixed localization of un- and hyper-reproductivity in the tail of a generational population evidently induced the continuous survival of outliers and extremes. These hypothetical considerations and mathematical simulations may suggest the significance of stochastic epistasis as the essential genetic background of complex human diversity.

The origin of complex human diversity: Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability

The continuing prevalence of a highly heritable and hypo-reproductive extreme tail of a human neurobehavioral quantitative diversity suggests the reproductive majority retains the genetic mechanisms for extremes. From the perspective of stochastic epistasis, the effect of an epistatic modifier variant can randomly vary in both phenotypic value and effect direction among carriers depending on the genetic identity and the modifier carriers are ubiquitous in the population. The neutrality of the mean genetic effect in carriers ensures the survival of the variant under selection pressures. Functionally or metabolically related modifier variants make an epistatic network module and dozens of modules may be involved in the phenotype. To assess the significance of stochastic epistasis, a simplified module-based model was simulated. The individual repertoire of the modifier variants in a module also contributes in genetic identity, which determines the genetic contribution of each carrier modifier. Because the entire contribution of a module to phenotypic outcome is unpredictable in the model, the module effect represents the total contribution of related modifiers as a stochastic unit in simulations. As a result, the intrinsic compatibility between distributional robustness and quantitative changeability could mathematically be simulated using the model. The artificial normal distribution shape in large-sized simulations was preserved in each generation even if the lowest fitness tail was non-reproductive. The robustness of normality across generations is analogous to the real situation of complex human diversity, including neurodevelopmental conditions. The repeated regeneration of a non-reproductive extreme tail may be essential for survival and change of the reproductive majority, implying extremes for others. Further simulation to illustrate how the fitness of extreme individuals can be low across generations may be necessary to increase the plausibility of this stochastic epistasis model.