A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge
Abstract
:1. Introduction
2. Methods
3. Results
3.1. Literature Search and Study Selection
3.2. HARs and Neurodevelopment
3.2.1. HARs’ Function in Neurodevelopment
3.2.2. Genes Associated with HARs and Their Expression and Functional Patterns
3.2.3. Regulatory Effect of Candidate HARs on Their Proximal Genes
3.3. HARs and Brain and Cognitive Phenotypes
3.4. HARs and Psychiatric Disorders
3.4.1. HARs in Schizophrenia
3.4.2. HARs in Other Neurodevelopment-Related Psychiatric Disorders and Syndromes
4. Discussion
5. Future Perspectives
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Main Objective (Methodology) | Main Results |
---|---|
Doan et al. [52] To characterise the functions of HARs in neurodevelopment (in silico analyses) |
|
Won et al. [58] To map and characterise HAR expression patterns, tissue, and cell specificity (in silico analyses) |
|
Uerbbing et al. [59] To study the effect of HAR variability in human neurogenesis (massively parallel reporter assay (MPRA) in human neural stem cells) |
|
Girskis et al. [60] To study HARs’ effect on the recent evolution of the human cerebral cortex (Capture MPRAs in human neural stem cells and neurospheres) |
|
HAR | Gene—Function | Validation Methodology | Main Results |
---|---|---|---|
HAR1 [47] | HAR1F and HAR1R (Highly Accelerated Region 1A and 1B, 20q13.33) Non-Protein-Coding RNAs. Unknown function. | Expression assay on human embryonic and adult brain. Comparative expression analysis in embryonic macaque, mouse, and human brains |
|
HACN96, HAR202, 2xHAR142, HAR89, 2xHAR223, 2xHAR157, 2xHAR122, HAR96, HACNS658, HAR189, HACNS553, HAR21, HACNS221, HAR173 [62,63] | NPAS3 (Neuronal PAS Domain Protein 3, 14q13.1) Transcription factor involved in the control of neurosignalling pathways during neurogenesis. | Expression assays in transgenic zebrafish and mice. Comparative expression of human, chimpanzee, and mouse HAR orthologs. Hybridisation in transgenic mice |
|
HAR31, HACNS174, HACNS369 [64] | AUTS2 (Autism Susceptibility Candidate 2, 7q11.22) Transcription factor involved in neurodevelopmental regulation, axon and dendrite elongation, and neuronal migration. | Targeted expression assays in transgenic zebrafish and mice |
|
HARE5 [65] | FZD8 (Frizzled Class Receptor 8, 10p11.21) Receptor in the WNT pathway implicated in cortical development. | Comparative expression of human and chimpanzee HAR orthologs in transgenic mice |
|
HAR-HSTR1 [61] | HSTR1 (Human-Specific Tandem Repeat 1, 20p) Non-Protein-Coding RNA. Unknown function. Non-annotated gene. | Targeted expression assays in HEK293T cells. Comparative expression of human, chimpanzee, gorilla, and orangutan HAR orthologs through luciferase reporter assays |
|
HAR426 [52] | CUX1 (Cut Like Homeobox 1, 7q22.1) Transcription factor involved in the control of neuronal differentiation. | Mutant and wild-type HAR mutation effect through luciferase reporter assays in mouse neural-precursor-like cells |
|
HAR169 [52] | PTBP2 (Polypyrimidine Tract Binding Protein 2, 1p21.3) RNA-binding protein and brain-specific splicing regulator essential for neuronal differentiation. | Mutant and wild-type HAR mutation effect through luciferase reporter assays in mouse neural-precursor-like cells. Massively parallel reporter assays in mouse neurospheres |
|
HAR1325 [52] | GPC4 (Glypican Proteoglycan 4, Xq26.2) Protein essential for excitatory synapse development in mice and dosage-sensitive gene in adult human brain. | Mutant and wild-type HAR mutation effect through luciferase reporter assays in mouse neural-precursor-like cells. Massively parallel reporter assays in mouse neurospheres |
|
HAR4 [58] | GLI2 (GLI family zinc finger 2, 2q14.2) Transcription factor in the Sonic Hedgehog (Shh) pathway critical for neural tube formation. Involved in cell growth and specialisation. | Targeted expression in primary human neural progenitor cells |
|
HAR1225 [58] | GLI3 (GLI family zinc finger 3, 7p14.1) Transcription factor in the Shh pathway critical for neural tube formation. Essential for dorsal–ventral patterning of telencephalon and cortex formation in humans. | Targeted expression in primary human neural progenitor cells |
|
HAR342 [58] | TBR1 (T-Box Brain Transcription Factor 1, 2q24.2) Transcriptional factor repressor involved in neuronal migration, laminar and areal identity, and axonal projection. | Targeted expression in primary human neural progenitor cells |
|
HAR2635, HAR2636 [60] | PPP1R17 (Protein Phosphatase 1 Regulatory Subunit 17, 7p14.3) Phosphatase inhibitor involved in neural progenitor cell proliferation and expression regulation in the developing human cortex. | Targeted chromatin conformation capture 3C interaction analysis |
|
Main Objective | Main Methodology | Main Results |
---|---|---|
Wei et al. [66] To study the evolutionary genetics of cortical expansion using HAR gene expression | Correlation analyses of HAR genes expression with cortical expansion differences from human vs. chimpanzee (sMRI data) and human vs. primates comparative gene expression. Association analyses of HAR and HAR brain genes with DMN variability (resting state fMRI data), intelligence, and sociability (based on GWAS data) |
|
Li et al. [67] To study the evolutionary genetics of brain connectivity using HAR brain gene expression | Correlation analyses of HAR brain gene expression with functional connectivity data (resting state fMRI data) |
|
Luppi et al. [68] To study the evolutionary genetics of redundant and synergistic information organization using HAR brain gene expression | Correlation analyses of HAR brain gene expression with the spatial distribution of synergistic and redundant brain interactions (resting state fMRI data) |
|
Cheung et al. [69] To test whether genes associated with intelligence are enriched in HARs | Enrichment analyses on HARs, brain expression, and their interaction on intelligence (based on GWAS data) |
|
Main Objective | Main Methodology | Main Results |
---|---|---|
Schizophrenia | ||
Xu et al. [71] To study HAR enrichment on common variability associated with SCZ | HAR enrichment analysis in SCZ (based on GWAS data) and gene co-expression network analyses |
|
Srinivassan et al. [73] To study HAR enrichment of common variability associated with SCZ | HAR enrichment analysis in SCZ (based on GWAS data) |
|
Wei et al. [66] To study the association of HAR genes and HAR brain genes with SCZ | Examination of potential associations of HAR and HAR brain genes with SCZ variability (based on GWAS data) |
|
Cheung et al. [69] To study HAR gene enrichment on genes associated with neuropsychiatric disorders conditional to developmental gene-expression patterns | HAR gene enrichment analyses in five neuropsychiatric disorders (SCZ, BPD, ASD, MDD, and ADHD, based on GWAS data) conditional to gene expression in five developmental stages |
|
Erady et al. [76] To investigate nORF associated with HARs in the genetic architecture of SCZ and BPD | Assess the overlap between nORF and nORF differentially expressed in SCZ and BPD and HARs. nORD and HARs overlap enrichment analyses in SCZ and BPD (based on GWAS data) |
|
Tolosa et al. [70] To study the association of common variants in HAR1F gene with SCZ risk and AH in SCZ | Case–control association study (285 SCZ-spectrum disorders [221 AH and 64 no AH] and 337 HC) of HAR1F gene (six variants genotyped) with SCZ risk |
|
González-Peñas et al. [72] To study the association of common and rare variants in NPAS3 HARs with SCZ risk | Case–control association study (538 SCZ and 539 HC) of NPAS3 gene (26 variants genotyped) with SCZ risk |
|
Bhattacharyya et al. [74,75] To assess the association of variants in HARs with SCZ and cognitive performance | Case–control association study (Discovery: 494 patients and 436 healthy controls (HC); Replication: 552 patients and 551 HC) of HARs (49 variants genotyped) with SCZ risk. Case–control association study in a subsample (331 patients and 235 HC) of HARs (49 variants genotyped) with cognition variability |
|
Other neurodevelopmental psychiatric disorders and related syndromes | ||
Doan et al. [52] To evaluate the mutational landscape of HARs and their contribution to ASD | HAR gene mapping through in silico chromatin interaction data. Assessment of copy number variants (CNVs) in 2100 ASD-sibs sample. Assessment of rare mutations in HARs through whole-genome sequencing in 218 ASD families |
|
Won et al. [58] To study the role of HAR genes in the susceptibility for neurodevelopmental disorders | HAR enrichment analysis with genes harbouring loss-of-function variants in ASD, SCZ, and DD data |
|
Wei et al. [66] To study the association of HAR genes and HAR brain genes with ASD variability and brain structural changes found in psychiatric disorders | Examination of potential associations of HAR and HAR brain genes with genes associated with ASD (based on rare variants of brain disorders). Correlation analyses of HAR brain gene expression with structural alterations across psychiatric disorders (sMRI data on SCZ, BPD, ASD, MDD, OCD) |
|
Takahashi et al. [77] To identify the molecular pathways associated with delirium and test the enrichment of HAR genes | Functional enrichment analysis of HAR genes in delirium-associated genes (obtained from the toxicogenomics database) |
|
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Guardiola-Ripoll, M.; Fatjó-Vilas, M. A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge. Int. J. Mol. Sci. 2023, 24, 3597. https://doi.org/10.3390/ijms24043597
Guardiola-Ripoll M, Fatjó-Vilas M. A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge. International Journal of Molecular Sciences. 2023; 24(4):3597. https://doi.org/10.3390/ijms24043597
Chicago/Turabian StyleGuardiola-Ripoll, Maria, and Mar Fatjó-Vilas. 2023. "A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge" International Journal of Molecular Sciences 24, no. 4: 3597. https://doi.org/10.3390/ijms24043597
APA StyleGuardiola-Ripoll, M., & Fatjó-Vilas, M. (2023). A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge. International Journal of Molecular Sciences, 24(4), 3597. https://doi.org/10.3390/ijms24043597