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.

Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations

“…These HAR genes have been suggested to have a vital role in human brain development (76) and may induce multiple brain disorders (77). As a previous review suggested (29), HARs are involved in the genetic signature of neurodevelopmental-related psychiatric disorders including schizophrenia. Accordantly, we found an association between the S-A epicenter axis of EOS and brain expression maps of HAR genes.…”

“…This hypothesis posits that these mental illnesses emerge as costly by-products of human evolution (27). For example, the human accelerate region (HAR) genes, i.e., the human-specific genes located in the accelerated diverging HARs between humans and chimpanzee ancestors (28), may harbor common genetic determinants shared across different psychiatric disorders (29). Notably, the availability of whole-brain gene expression atlases from the Allen Human Brain Atlas ([AHBA]; http://human.brain-map.org) microarray dataset (30) offers an unprecedented chance to bridge the brain connectome and microscale gene transcriptomes (31).…”

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

“…Through a neuroimaging genetic approach, we have evaluated the SZ’s polygenic burden of human-specific evolutionary markers such as HARs on brain-based phenotypes closely related to the pathophysiology of the disorder. Although studies on HARs are an emerging field, as a recent review by our group highlights 57 , and the expression profiles of HARs-brain genes have been studied in relation to brain structural changes across different psychiatric disorders 48 , our study is the first to assess the effect of HARs genetic variability on brain cortical measures in patients with SZ and healthy controls. These analyses provide evidence of the impact of foetal active regulatory HARs on the cortical surface area of different brain regions in patients with SZ.…”

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

“…After a first study had identified and partially characterized a "human accelerated region" (HAR) [42], further HARs were investigated and indeed, as one important discovery, their proximity to neuropsychiatric disease genes was revealed [39,[148][149][150][151][152][153][154]. Since many HAR-associated genes are regulators and hubs in transcriptional networks, their differential expression would affect many other genes and cellular processes, suggesting outsized effects caused by noncoding HAR mutations.…”