Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 433 records · Page 24Linked to original sources

bioRxiv2024

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

BackgroundPathogens have been one of the primary sources of natural selection affecting modern humans. The footprints of historical selection events - "selective sweeps" - can be detected in the genomes of present-day individuals. Previous analyses of 629 samples from the 1000 Genomes Project suggested that an ancient coronavirus epidemic [~]20,000 years ago drove multiple selective sweeps in the ancestors of present-day East Asians, but not in other worldwide populations. ResultsUsing a much larger genetic dataset of 76,719 unrelated individuals from each of the China Kadoorie Biobank (CKB) and UK Biobank (UKB) to identify regions of long-range linkage disequilibrium, we further investigated signatures of past selective sweeps and how they reflect previous viral epidemics. Using independently-curated lists of human host proteins which interact physically or functionally with viruses (virus-interacting proteins; VIPs), we found enrichment in CKB for regions of long-range linkage disequilibrium at genes encoding VIPs for coronaviruses, but not DNA viruses. By contrast, we found no clear evidence for any VIP enrichment in UKB. These findings were supported by additional analyses using saltiLASSi, a selection-scan method robust to false positives caused by demographic events. By contrast, for GWAS signals for SARS-Cov2 susceptibility (critical illness, hospitalisation, and reported infection), there was no difference between UKB and CKB in the number located at or near signals of selection, as expected for a novel virus which has had no opportunity to impact the CKB/UKB study populations. ConclusionsTogether, these results provide evidence of selection events consistent with historical coronavirus epidemic(s) originating in East Asia. These results show how biobank-scale datasets and evolutionary genomics theory can provide insight into the study of past epidemics. The results also highlights how historic infectious diseases epidemics can shape the genetic architecture of present-day human populations.

genomics↗

bioRxiv2024

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain. Recent developments in tissue clearing have enabled unprecedented mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rates values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a new approach based on large-scale fluo-rescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1000 Hz and spatial resolution reaching 5.4 {micro}m. Using Pia-FLOW, we provide detailed maps of flow velocity, direction and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

neuroscience↗

bioRxiv2024

Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes

A major challenge in human genomics is to decipher the context specific relationship of sequence to function. However, existing tools for locus specific hypermutation and evolution in the native genome context are limited. Here we present a novel programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000 bp) genomic intervals. We applied HACE to identify mutations in MEK1 that confer kinase inhibitor resistance, to dissect the impact of individual variants in SF3B1-dependent mis-splicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions. One Sentence SummaryWe developed a tool for continuous, long-range, targeted diversification of endogenous mammalian genomes and used it to explore the function of genetic variants in both coding and non-coding regions.

genetics↗

bioRxiv2024

AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis

Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we report OVOL1/Ovol1 as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, and Ovol1 deletion in keratinocytes hampers AhRs barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1s direct downstream targets genome-wide, and provide in vivo evidence for Id1s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal {gamma}{delta}T cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.

molecular biology↗

bioRxiv2024

A unified model for cell-type resolution genomics from heterogeneous omics data

The vast majority of population-scale genomic datasets collected to date consist of "bulk" samples obtained from heterogeneous tissues, reflecting mixtures of different cell types. In order to facilitate discovery at the cell-type level, there is a pressing need for computational deconvolution methods capable of leveraging the multitude of underutilized bulk profiles already collected across various organisms, tissues, and conditions. Here, we introduce Unico, a unified cross-omics method designed to deconvolve standard 2-dimensional bulk matrices of samples by features into 3-dimensional tensors representing samples by features by cell types. Unico stands out as the first principled model-based deconvolution method that is theoretically justified for any heterogeneous genomic data. Through the deconvolution of bulk gene expression and DNA methylation datasets, we demonstrate that the transferability of Unico across different data modalities translates into superior performance compared to existing approaches. This advancement enhances our capability to conduct powerful large-scale genomic studies at cell-type resolution without the need for cell sorting or single-cell biology. An R implementation of Unico is available on CRAN.

genomics↗

bioRxiv2024

Ciliary length regulation by intraflagellar transport in zebrafish

How cells regulate the size of their organelles remains a fundamental question in cell biology. Cilia, with their simple structure and surface localization, provide an ideal model for investigating organelle size control. However, most studies on cilia length regulation are primarily performed on several single-celled organisms. In contrast, the mechanism of length regulation in cilia across diverse cell types within multicellular organisms remains a mystery. Similar to humans, zebrafish contain diverse types of cilia with variable lengths. Taking advantage of the transparency of zebrafish embryos, we conducted a comprehensive investigation into intraflagellar transport (IFT), an essential process for ciliogenesis. By generating a transgenic line carrying Ift88-GFP transgene, we observed IFT in multiple types of cilia with varying lengths. Remarkably, cilia exhibited variable IFT speeds in different cell types, with longer cilia exhibiting faster IFT speeds. This increased IFT speed in longer cilia is likely not due to changes in common factors that regulate IFT, such as motor selection, BBSome proteins, or tubulin modification. Interestingly, longer cilia in the ear cristae tend to form larger IFT compared to shorter spinal cord cilia. Reducing the size of IFT particles by knocking down Ift88 slowed IFT speed and resulted in the formation of shorter cilia. Our study proposes an intriguing model of cilia length regulation via controlling IFT speed through the modulation of the size of the IFT complex. This discovery may provide further insights into our understanding of how organelle size is regulated in higher vertebrates.

cell biology↗

bioRxiv2024

Multiplex Imaging Reveals Novel Subcellular, Microenvironmental, and Racial Patterns of MRTFA/B Activation in Invasive Breast Cancers and Metastases

Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin related transcription factors A and B (MRTFA/B) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we used a combination of multiplexed immunofluorescence and bioinformatics analyses to show that MRTFA/B are concurrently activated in tumor cells, but they show distinct patterns of expression across different histological subtypes and in the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen presenting cells (APCs) and its expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR). These results provide unique insights into how MRTFA and MRTFB can promote metastasis in human cancer, into the racial disparities of their expression patterns, and their function within the complex breast cancer TME. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/573909v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@12037b3org.highwire.dtl.DTLVardef@28e2feorg.highwire.dtl.DTLVardef@4e95e1org.highwire.dtl.DTLVardef@152019b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Complementation testing identifies causal genes at quantitative trait loci underlying fear related behavior

Knowing the genes involved in quantitative traits provides a critical entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. Here we address a key step towards that goal by deploying a test that directly queries whether a gene mediates the effect of a quantitative trait locus (QTL). To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six QTLs, and identified six genes. Four genes, Lsamp, Ptprd, Nptx2 and Sh3gl, have known roles in synapse function; the fifth gene, Psip1, is a transcriptional co-activator not previously implicated in behavior; the sixth is a long non-coding RNA 4933413L06Rik with no known function. Single nucleus transcriptomic and epigenetic analyses implicated excitatory neurons as likely mediating the genetic effects. Surprisingly, variation in transcriptome and epigenetic modalities between inbred strains occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results open a bottleneck in using genetic mapping of QTLs to find novel biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.

genetics↗

bioRxiv2024

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

cancer biology↗

bioRxiv2023

Rewriting regulatory DNA to dissect and reprogram gene expression

Regulatory DNA sequences within enhancers and promoters bind transcription factors to encode cell type-specific patterns of gene expression. However, the regulatory effects and programmability of such DNA sequences remain difficult to map or predict because we have lacked scalable methods to precisely edit regulatory DNA and quantify the effects in an endogenous genomic context. Here we present an approach to measure the quantitative effects of hundreds of designed DNA sequence variants on gene expression, by combining pooled CRISPR prime editing with RNA fluorescence in situ hybridization and cell sorting (Variant-FlowFISH). We apply this method to mutagenize and rewrite regulatory DNA sequences in an enhancer and the promoter of PPIF in two immune cell lines. Of 672 variant-cell type pairs, we identify 497 that affect PPIF expression. These variants appear to act through a variety of mechanisms including disruption or optimization of existing transcription factor binding sites, as well as creation of de novo sites. Disrupting a single endogenous transcription factor binding site often led to large changes in expression (up to -40% in the enhancer, and -50% in the promoter). The same variant often had different effects across cell types and states, demonstrating a highly tunable regulatory landscape. We use these data to benchmark performance of sequence-based predictive models of gene regulation, and find that certain types of variants are not accurately predicted by existing models. Finally, we computationally design 185 small sequence variants ([≤]10 bp) and optimize them for specific effects on expression in silico. 84% of these rationally designed edits showed the intended direction of effect, and some had dramatic effects on expression (-100% to +202%). Variant-FlowFISH thus provides a powerful tool to map the effects of variants and transcription factor binding sites on gene expression, test and improve computational models of gene regulation, and reprogram regulatory DNA.

genetics↗

bioRxiv2023

Tracking SARS-CoV-2 variants of concern in wastewater: an assessment of nine computational tools using simulated genomic data

Wastewater-based surveillance (WBS) is an important epidemiological and public health tool for tracking pathogens across the scale of a building, neighbourhood, city, or region. WBS gained widespread adoption globally during the SARS-CoV-2 pandemic for estimating community infection levels by qPCR. Sequencing pathogen genes or genomes from wastewater adds information about pathogen genetic diversity which can be used to identify viral lineages (including variants of concern) that are circulating in a local population. Capturing the genetic diversity by WBS sequencing is not trivial, as wastewater samples often contain a diverse mixture of viral lineages with real mutations and sequencing errors, which must be deconvoluted computationally from short sequencing reads. In this study we assess nine different computational tools that have recently been developed to address this challenge. We simulated 100 wastewater sequence samples consisting of SARS-CoV-2 BA.1, BA.2, and Delta lineages, in various mixtures, as well as a Delta-Omicron recombinant and a synthetic "novel" lineage. Most tools performed well in identifying the true lineages present and estimating their relative abundances, and were generally robust to variation in sequencing depth and read length. While many tools identified lineages present down to 1% frequency, results were more reliable above a 5% threshold. The presence of an unknown synthetic lineage, which represents an unclassified SARS-CoV-2 lineage, increases the error in relative abundance estimates of other lineages, but the magnitude of this effect was small for most tools. The tools also varied in how they labelled novel synthetic lineages and recombinants. While our simulated dataset represents just one of many possible use cases for these methods, we hope it helps users understand potential sources of noise or bias in wastewater sequencing data and to appreciate the commonalities and differences across methods.

bioinformatics↗

bioRxiv2023

Effects of fructooligosaccharides and Saccharomyces boulardii on the compositional structure and metabolism of gut microbiota in students

Fructooligosaccharides (FOS) are a common prebiotic widely used in functional foods. Meanwhile, Saccharomyces boulardii is a fungal probiotic frequenly used in the clinical treatment of diarrhea. Compared with single use, the combination of prebiotics and probiotics may be more effective in regulating gut microbiota. Hence, the combined use of prebiotics and probiotics has become a hot spot in synbiotics research in recent years. The present study aimed to investigate the effects of FOS and S. boulardii-- alone or in combination--on the structure and metabolism of the gut microbiota in healthy primary and secondary school students using an in vitro fermentation model. The results indicated that S. boulardii alone could not effectively regulate the community structure and metabolism of the microbiota. However, both FOS and the combination of FOS and S. boulardii could effectively regulate the microbiota, significantly inhibiting the growth of Escherichia-Shigella and Bacteroides, and controlling the production of the gases including H2S and NH3. In addition, both FOS and the combination could significantly promote the growth of Bifidobacteria and Lactobacillus, lower environmental pH, and enhance several physiological functions related to synthesis and metabolism. Nevertheless, the combination had more unique benefits as it promoted the growth of Lactobacillus, significantly increased CO2 production and enhanced the functional pathways of carbon metabolism and pyruvic acid metabolism. These findings provide guidance for clinical application and a theoretical basis for the development of synbiotic preparations.

microbiology↗

bioRxiv2023

Temporal recording of mammalian development and precancer

Key to understanding many biological phenomena is knowing the temporal ordering of cellular events, which often require continuous direct observations [1, 2]. An alternative solution involves the utilization of irreversible genetic changes, such as naturally occurring mutations, to create indelible markers that enables retrospective temporal ordering [3-8]. Using NSC-seq, a newly designed and validated multi-purpose single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, while incorporating assigned cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during murine embryonic development and identified new intestinal epithelial progenitor states by their unique genetic histories. NSC-seq analysis of murine adenomas and single-cell multi-omic profiling of human precancers as part of the Human Tumor Atlas Network (HTAN), including 116 scRNA-seq datasets and clonal analysis of 418 human polyps, demonstrated the occurrence of polyancestral initiation in 15-30% of colonic precancers, revealing their origins from multiple normal founders. Thus, our multimodal framework augments existing single-cell analyses and lays the foundation for in vivo multimodal recording, enabling the tracking of lineage and temporal events during development and tumorigenesis.

developmental biology↗

bioRxiv2023

ARBUR: a Machine Learning-based Analysis System for Relating Behaviors and Ultrasonic Vocalizations of Rats

Deciphering how different types of behavior and ultrasonic vocalizations (USVs) of rats interact can yield insights into the neural basis of social interaction. However, the behavior-vocalization interplay of rats remains elusive because of the challenges of relating the two communication media in complex social contexts. Here, we propose a machine learning-based analysis system (ARBUR) that can cluster without bias both non-step (continuous) and step USVs, hierarchically detect eight types of behavior of two freely behaving rats with high accuracy, and locate the vocal rat in 3-D space. By simultaneously recording the video and ultrasonic streams of two freely behaving rats, ARBUR reveals that rats communicate via distinct USVs when engaging in different types of social behavior. Moreover, we show that ARBUR can not only automatically reveal the well-understood behavior-associated vocalizations that were carefully concluded by other behavioral researchers, but also hold the promise to indicate novel findings that can be hardly found by manual analysis, especially regarding step USVs and the active/passive rat-associated USVs during easy-to-confuse social behaviors. This work highlights the potential of machine learning algorithms in automatic animal behavioral and acoustic analysis and could help mechanistically understand the interactive influence between the behaviors and USVs of rats.

animal behavior and cognition↗

bioRxiv2023

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.

cancer biology↗

bioRxiv2023

An Integrated Optogenetic and Bioelectronic Platform for Regulating Cardiomyocyte Function

We report an integrated optogenetic and bioelectronic platform for stable and long-term modulation and monitoring of cardiomyocyte function in vitro. Optogenetic inputs were achieved through expression of a photoactivatable adenylyl cyclase (bPAC), that when activated by blue light caused a dose-dependent and time-limited increase in autonomous cardiomyocyte beat rate. Bioelectronic readouts were achieved through an integrated planar multi-electrode array (MEA) that provided real-time readouts of electrophysiological activity from 32 spatially-distinct locations. Irradiation at 27 W/mm2 resulted in a ca. 14% increase in beat rate within 20-25 minutes, which remained stable for at least 2 hours. The beating rate could be cycled through repeated "on" and "off" states, and its magnitude was a monotonic function of irradiation intensity. Our integrated platform opens new avenues in bioelectronic medicine, including closedloop feedback systems, with potential applications for cardiac regulation including arrhythmia diagnosis and intervention. TeaserA system that integrates optogenetic stimulation and bioelectronic recording capabilities allows for on-demand regulation of cardiac cell function.

bioengineering↗

bioRxiv2023

Comparison of chronic aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors and neuroimmune profile in mice

With the worldwide use of electronic cigarettes (e-cigarettes) as a substitution for tobacco, the effects of e-cigarette vapor exposure on human health have been investigated. However, the comparison of long-term effects of aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors has not been fully revealed. The present study examines the distinct effects of combustible cigarette and e-cigarette on anxiety, depression, cognition, and social behaviors. Here we found that the combustible cigarette induced the higher level of anxiety after long-term inhalation compared to the e-cigarettes with or without the tobacco flavor. Since the mechanism of action on the psychiatric behaviors entails the alterations on the neuroimmune-sensors and principal regulators such as glial cells, we further profiled the alterations of microglia and astrocytes by chronic inhalation of combustible tobacco cigarette, specifically the negative correlations between the IBA-1 level in the locus coeruleus (LC) and the latency to nest in VLT; as well as the GFAP level in LC and the open arm time in EPM were observed. Our current data provided an insight into the less impact of e-cigarettes on the anxiety-like behaviors and neuroimmune activation compared to combustible tobacco cigarettes which is not related to the flavor in e-cigarette, and the modulation on the neuroimmune signals in LC could be a therapeutic target for smoking-related anxiety.

animal behavior and cognition↗

bioRxiv2023

Mapping the shared and unique structural asymmetry abnormalities of young children with autism and developmental delay/intellectual disability with normative models and their multimodal cascade

To understand the neural mechanism of autism spectrum disorder (ASD) concurrent with developmental delay/intellectual disability (DD/ID), it is essential to comprehensively take genetic, brain, and behavioural measurements as a whole and focus on subjects at early age. However, such research is still lacking. Here, using the sMRI data of 1030 children under 8 years old, we employed developmental normative models to explore the atypical development of gray matter volume (GMV) asymmetry in individuals with ASD without DD/ID, ASD with DD/ID and DD/ID, and their associations with neurophysiological measures and transcription profiles. By computing the individual deviations from typical controls, we observed an ASD-specific abnormal GMV laterality pattern that was more rightwards in the inferior parietal cortex and precentral cortex and noted abnormal within-group heterogeneity in the temporal pole. Specifically, ASD with DD/ID children exhibited more regional abnormalities; ASD without DD/ID children showed higher within-group variability; while children with DD/ID showed no significant abnormalities. However, there were no significant differences among the three groups. The GMV laterality of ASD without DD/ID children was associated with ASD symptoms, whereas that of ASD with DD/ID children was associated with both ASD symptoms and verbal IQ. Last, the GMV laterality of the ASD with DD/ID, ASD without DD/ID, and DD/ID groups was associated with shared and unique gene expression profiles, but the associations of the latter two groups with intellectual genes showed opposite effects. Our findings illustrated the atypical development of regional structural lateralization in autistic children, which is associated with upstream genes and downstream behavioural performance. The differences and similarity between ASD and DD/ID additionally improve our standing to the neural mechanism of neurodevelopmental disorders comorbidity.

neuroscience↗