The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Tail of a Complex Dimensional Trait

The Origin of Population Diversity: Stochastic Interactions between a Modifier Variant and the Individual Genetic Background

“…Both the active directional trend by de novo epistatic modifiers and the passive directional trend by repeated purge of the non-fittest tail may affect the position of the distribution in the nonlinear relation to fecundity probability, especially through a population bottleneck or reproductive isolation of a smaller population. To predict the ongoing trends or future directional changes of the complex trait distributions, the presence of fitness benefits of border cases who is located in the transitional zone flanking to the non-fittest tail [11], a trade-off between the non-fittest outcomes and fitness benefits by expanding the range of complexity [74], and the role of female carriers of modifiers to maintain the non-fittest tail in the population distribution [75] should be involved in the consideration.…”

“…Even the degree of phenotypic penetrance of a major variant gene effect, the liability to dichotomous diagnosis, the latent period duration of later-onset diseases, clinical response to treatment, and both resistance and vulnerability to the pathogens, toxins, or mental stress can be illustrated by quantitative complexity [10]. The stochastic epistasis perspective was introduced to explain such human complex conditions [10] [11], and it is characterized by the phenotypic concordance in monozygotic twins in contrast to the discordance of "gene expression noise" and "random monoallelic expression" ( Table 1). Although involvement of environmental factors and the epigenetic factors is sometimes emphasized to explain the presence of discordant identical twin cases in some complex conditions [12], the stochastic epistasis can have a great role in complex conditions which have a disparity between monozygotic and dizygotic concordances.…”

“…Hundreds of candidate variants associated with complex conditions have recently been found, and most of these variants explain only a modest amount of the observed heritability ("missing heritability") [24]- [26]. The reported gene variants including de novo mutations are detected in a minor part of cases and sometimes show incomplete penetrance in family members and low result reproduction rate in different samples [11]. In addition, the modest genetic overlap among sub-domains in a condition [27] [28] may be indistinguishable from that among multiple other complex conditions [29] [30].…”

Quantitative Nature of Social Vulnerability and Autism: An Important Paradigm Shift in the DSM-5 for Autism Spectrum Disorder

“…The involvement of genetic factors is evident from the results of twin study, and many gene variants which seem to affect brain development and synaptic functions have been reported in association with ASD [7]. However, the reported gene variants are, at present, nothing but one of the concomitants in a small percentage of the cases [8]. There is as yet no qualitative biological marker which is cosegregated with ASD, and even the molecular deviations associated with the reported gene variants have not been confirmed [8].…”

“…However, the reported gene variants are, at present, nothing but one of the concomitants in a small percentage of the cases [8]. There is as yet no qualitative biological marker which is cosegregated with ASD, and even the molecular deviations associated with the reported gene variants have not been confirmed [8]. Because the apparent involvement of genetic factors or high heritability does not vindicate the condition as a diagnostic category [9], the evolutionary survived trait may be the dimensional diversity itself [8].…”