Enhancer Function and Evolutionary Roles of Human Accelerated Regions

Whalen, Sean; Pollard, Katherine S.

doi:10.1146/annurev-genet-071819-103933

Cited by 36 publications

(27 citation statements)

References 78 publications

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“…In line with these data, a number of genes that are regulated by HARs with empirically confirmed or bioinformatically predicted enhancer activity, are implicated in human-specific development of certain brain areas, including the cortex (9,23,26,46,47) [also reviewed in Levchenko et al (12)]. For example, Capra et al demonstrated that 60% of HARs are enhancers and bind at least one transcription factor different between human and chimpanzee (46).…”

Section: Human Accelerated Regions and Psychosismentioning

confidence: 88%

“…There are several different types of genetic variants present in Homo sapiens, but absent in all other primate, mammalian or vertebrate species, tested so far. The rationale for studying these human-specific variants is that they could be responsible for traits specific to our species, of which the human brain is the most outstanding (9,12,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). These sequence variants include humanspecific accelerated single nucleotide substitutions in evolutionarily conserved regions called human accelerated regions (HARs) (26)(27)(28)(29)(30)(31)(32).…”

Section: Human Accelerated Regions and Psychosismentioning

confidence: 99%

“…The rationale for studying these human-specific variants is that they could be responsible for traits specific to our species, of which the human brain is the most outstanding (9,12,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). These sequence variants include humanspecific accelerated single nucleotide substitutions in evolutionarily conserved regions called human accelerated regions (HARs) (26)(27)(28)(29)(30)(31)(32). HARs are short stretches of DNA, about 260 base pairs on average and to 97% non-coding (12).…”

Section: Human Accelerated Regions and Psychosismentioning

confidence: 99%

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The evolutionary origin of psychosis

Levchenko

Gusev²,

Rogaev³

2023

Front. Psychiatry

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Imagination, the driving force of creativity, and primary psychosis are human-specific, since we do not observe behaviors in other species that would convincingly suggest they possess the same traits. Both these traits have been linked to the function of the prefrontal cortex, which is the most evolutionarily novel region of the human brain. A number of evolutionarily novel genetic and epigenetic changes that determine the human brain-specific structure and function have been discovered in recent years. Among them are genomic loci subjected to increased rates of single nucleotide substitutions in humans, called human accelerated regions. These mostly regulatory regions are involved in brain development and sometimes contain genetic variants that confer a risk for schizophrenia. On the other hand, neuroimaging data suggest that mind wandering and related phenomena (as a proxy of imagination) are in many ways similar to rapid eye movement dreaming, a function also present in non-human species. Furthermore, both functions are similar to psychosis in several ways: for example, the same brain areas are activated both in dreams and visual hallucinations. In the present Perspective we hypothesize that imagination is an evolutionary adaptation of dreaming, while primary psychosis results from deficient control by higher-order brain areas over imagination. In the light of this, human accelerated regions might be one of the key drivers in evolution of human imagination and the pathogenesis of psychotic disorders.

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Section: Human Accelerated Regions and Psychosismentioning

confidence: 88%

Section: Human Accelerated Regions and Psychosismentioning

confidence: 99%

Section: Human Accelerated Regions and Psychosismentioning

confidence: 99%

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The evolutionary origin of psychosis

Levchenko

Gusev²,

Rogaev³

2023

Front. Psychiatry

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“…The relatively higher cognitive play and social communication abilities revealed here should thus be stressed to help caregivers conduct language studies of MWS patients. In humans, accelerated genomic regions (ARs, the fastest-evolving sequences in the genome) are postulated as having neurological functions, potentially related to the evolution of larger brains and language ( Whalen and Pollard, 2022 ). ARs have been identified as enriched in noncoding regions near genes with known speech functions in humans and vocal learning birds, including ZEB2 , and this convergent evolution might be an indication of the particular importance of ZEB2 in vocal acquisition ( Kamm et al, 2013 ; Oksenberg et al, 2013 ; Boyd et al, 2015 ; Cahill et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome

Wang²,

Wang³

et al. 2022

Front. Genet.

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Background: To report detailed knowledge about the clinical manifestations, genetic spectrum as well as physical, language, neurodevelopment features and genotype-phenotype correlations of Chinese patients with Mowat-Wilson syndrome (MWS).Methods: We retrospectively collected and analyzed clinical data for twenty-two patients with molecularly confirmed diagnoses. We used Gesell Developmental Schedules (GDS) to assess their neurodevelopment and the Diagnostic Receptive and Expressive Assessment of Mandarin-Infant & Toddler (DREAM-IT) to evaluate their language ability and compared the data with the two types of underlying pathogenic variations.Results: The height and weight of all patients were below the 75th percentile, and microcephaly was observed in 16 of 22 patients (72.7%). Four patients carrying chromosome deletions encompassing the ZEB2 gene were more severely affected. All MWS patients exhibited better performance in cognitive play and social communication than in receptive and expressive language. In the receptive language area, the types of words that children with MWS understood most were nouns, followed by adjectives and verbs.Conclusion: This study delineated the phenotypic spectrum of the largest MWS cohort in China and provided comprehensive profiling of their physical, language, neurodevelopment features and genotype-phenotype correlations.

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“…Human AUTS2 display nucleotide variants that define the human-Neanderthal sweep 3 and three human accelerated regions (HARs) 4,5 .…”

Section: Introductionmentioning

confidence: 99%

AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders

Lepagnol-Bestel

Loe-Mie

Bensaid

et al. 2022

Preprint

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Autism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features. The AUTS2 syndrome phenotype includes borderline to severe intellectual disability (ID), microcephaly and mild dysmorphic traits. Specific ASD-like features, including obsessive or ritualistic behaviours, are frequently displayed, although sociability is largely unaffected. Syndrome severity is worse when mutations are present in the 3' region (exons 9-19) of the AUTS2 gene. AUTS2 is also associated with alcohol consumption, heroin dependence, schizophrenia and dyslexia, using GWAS studies. Our working hypothesis is that AUTS2 expression during mammalian evolution can be instrumental to predict phenotypes linked to the disease. For that, we studied brain In Situ Hybridization (ISH) data in mouse, marmoset, human embryo and fetuses and sequences data of Neanderthal, Denisovan and modern humans. Developmental mouse brain expression is found in neocortex, hippocampus, thalamus, tegmentum and cerebellum suggesting a link linked with cognition, stereotypies and perseverative behaviors. Expression in amygdala and claustrum found in marmoset extend these phenotypes to anxiety and higher-order cognitive processes. In human embryos (8 weeks) and fetuses (15- and 19-weeks), we found AUTS2 expression in similar regions but also in medial, lateral and caudal ganglionic eminence, that are involved in the diversity of interneurons found in neocortex, hippocampus and striatum. Sequence comparison of AUTS2 locus in Neanderthal, Denisova and modern human reveals novel sites in regulatory regions of AUTS2. Altogether, these results suggest that ISH distribution along mammals is a novel phenotype-related biomarker useful for translational research.

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Enhancer Function and Evolutionary Roles of Human Accelerated Regions

Cited by 36 publications

References 78 publications

The evolutionary origin of psychosis

The evolutionary origin of psychosis

Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome

AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders

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