Evolution and dysfunction of human cognitive and social traits: A transcriptional regulation perspective

Abstract

Evolutionary changes in brain and craniofacial development have endowed humans with unique cognitive and social skills, but also predisposed us to debilitating disorders in which these traits are disrupted. What are the developmental genetic underpinnings that connect the adaptive evolution of our cognition and sociality with the persistence of mental disorders with severe negative fitness effects? We argue that loss of function of genes involved in transcriptional regulation represents a crucial link between the evolution and dysfunction of human cognitive and social traits. The argument is based on haploinsufficiency of many transcriptional regulator genes, which makes them particularly sensitive to loss-of-function mutations. We discuss how human brain and craniofacial traits evolved through partial loss of function (i.e., reduced expression) of these genes, a perspective compatible with the idea of human self-domestication. Moreover, we explain why selection against loss-of-function variants supports the view that mutation-selection-drift, rather than balancing selection, underlies the persistence of psychiatric disorders. Finally, we discuss testable predictions.

Sex Determination in Homo sapiens as a Multi-Step Process: Potential for Development of Variants and Sex Differences in Disease Risk

“…The evolution of cognition to the degree associated with Homo sapiens, the current humanoid dominating the planet, is not clear as to when and how various attributes evolved and were integrated into the current function level [discussed in [76][77][78][79][80][81]]. Furthermore, humans are very heterogenous at multiple levels [discussed in [32]], which is a survival strength, and this also likely extends to various cognitive abilities.…”

A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans

“…Although it has been widely hypothesized that natural selection for human-specific traits has increased human disease risk 46,47,[79][80][81] , unambiguous evidence for this has been lacking. While there is strong evidence linking natural selection on within-human genetic variation to disease risk (e.g.…”

“…First, down-regulation of ASD-linked genes may have led to uniquely human phenotypes. For example, haploinsufficiency of many ASD-linked genes is associated with developmental delay 47 , so their down-regulation could have contributed to the slower postnatal brain development in humans compared to chimpanzees. Alternatively, capacity for speech production and comprehension are unique to or greatly expanded in humans and often impacted in ASD and SCZ 53,88 .…”

“…From an evolutionary perspective, it has been proposed that ASD and SCZ may be unique to humans [45][46][47] . This is primarily based on two main lines of reasoning.…”

“…Overall, evidence suggests that ASD and SCZ may be particularly prevalent in humans, but the factors underlying this increased prevalence remain unknown. Positive selection-also known as adaptive evolution-of brain-related traits in the human lineage has been proposed to underlie this increase [45][46][47]59,60 . Although this idea is supported by the links between HARs (many of which are thought to have been positively selected 56 ) and ASD and SCZ, there is no direct evidence for positive selection on the expression of genes linked to ASD and SCZ.…”