A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge

Abstract

Schizophrenia is a psychiatric disorder that results from genetic and environmental factors interacting and disrupting neurodevelopmental trajectories. Human Accelerated Regions (HARs) are evolutionarily conserved genomic regions that have accumulated human-specific sequence changes. Thus, studies on the impact of HARs in the context of neurodevelopment, as well as with respect to adult brain phenotypes, have increased considerably in the last few years. Through a systematic approach, we aim to offer a comprehensive review of HARs' role in terms of human brain development, configuration, and cognitive abilities, as well as whether HARs modulate the susceptibility to neurodevelopmental psychiatric disorders such as schizophrenia. First, the evidence in this review highlights HARs' molecular functions in the context of the neurodevelopmental regulatory genetic machinery. Second, brain phenotypic analyses indicate that HAR genes' expression spatially correlates with the regions that suffered human-specific cortical expansion, as well as with the regional interactions for synergistic information processing. Lastly, studies based on candidate HAR genes and the global "HARome" variability describe the involvement of these regions in the genetic background of schizophrenia, but also in other neurodevelopmental psychiatric disorders. Overall, the data considered in this review emphasise the crucial role of HARs in human-specific neurodevelopment processes and encourage future research on this evolutionary marker for a better understanding of the genetic basis of schizophrenia and other neurodevelopmental-related psychiatric disorders. Accordingly, HARs emerge as interesting genomic regions that require further study in order to bridge the neurodevelopmental and evolutionary hypotheses in schizophrenia and other related disorders and phenotypes.

Keywords: HARs; autism; brain configuration; cognitive abilities; evolution markers; human accelerated regions; human neurodevelopment; schizophrenia.

Figure 1

Flow diagram of the literature search and article selection.

Figure 2

Graphical summary of Human Accelerated Regions’ (HARs) impact on neurodevelopment, brain configuration, and associated psychiatric disorders. Middle panel: HARs are evolutionarily conserved genomic regions across mammals’ evolution that accumulated human-specific (H) changes since the divergence from chimpanzees (C). Molecular studies evidence that HARs function as transcription factor binding sites (TFBS) or transcription factors (TF) of genes involved in neurodevelopmental pathways [52,58,59,60]. Top panel: The key roles of HARs in the neurodevelopmental gene regulatory machinery underlie the human-specific neurodevelopmental characteristics sustaining human-specific brain architecture, information processing, and variability in neural integration, brain traits, which in turn are associated with different psychiatric disorders [66,67,68]. Bottom panel: Common and rare genetic variability in HARs and HAR genes is related to changes in the neurodevelopmental trajectories, and therefore, sustains the inherent human variability in cognition, intelligence, behaviour, and sociability traits [66,69], but also the neural dysfunction observed in the neurodevelopmental disorder continuum. Additionally, the described effect of HAR genomic variability on the genetic determinants underlying schizophrenia and other neurodevelopmental psychiatric disorders [52,58,66,69,71,73] strengthens the paramount role of HARs in the neurodevelopmental machinery.