Biology subjects

Gandal, M.

Publications and source records attributed to Gandal, M..

8 recordsLinked to original sources

bioRxiv2026

scRBP infers cell-specific RNA-binding protein regulons from single-cell transcriptomes at gene and isoform resolution

Single-cell regulatory network inference remains dominated by transcription factors, despite RNA-binding proteins (RBPs) orchestrating major aspects of transcriptional regulation. We present scRBP, a framework that infers motif-supported RBP regulons from short- and long-read single-cell transcriptomes at gene and isoform resolution, resolves targets by transcript region (5'UTR, CDS, intron, 3'UTR), scores regulon activity in individual cells, and tests common- and rare-variant association against matched empirical nulls. From 20,746 motifs for 616 RBPs, scRBP recovered experimentally defined targets across 223 ENCODE eCLIP datasets at gene and isoform level. Across 30 tissues, transcript-region preferences separated 3'UTR-associated stability factors from intron-dominant splicing regulators. In published genome-scale CRISPRi Perturb-seq data, scRBP-inferred targets were over-represented among genes responding to RBP knockdown (1.4-2.5-fold across 161 RBPs; FDR<2x10-4). Across 6.2 million cells and 50 traits, scRBP prioritized cell-specific post-transcriptional programs linking human genetic risk to development and disease.

genetics↗

bioRxiv2022

Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches in postnatal mouse somatosensory cortex (S1), we find that parvalbumin (PV) IN precursors are hypoactive and decoupled from excitatory neurons in Fmr1-/- mice, a model of Fragile X Syndrome (FXS). This leads to a loss of PV-INs in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1-/- mice restores PV density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering a novel allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

neuroscience↗

bioRxiv2021

Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data

Gene expression at the individual cell-level resolution, as quantified by single-cell RNA-sequencing (scRNA-seq), can provide unique insights into the pathology and cellular origin of diseases and complex traits. Here, we introduce single-cell Disease Relevance Score (scDRS), an approach that links scRNA-seq with polygenic risk of disease at individual cell resolution without the need for annotation of individual cells to cell types; scDRS identifies individual cells that show excess expression levels for genes in a disease-specific gene set constructed from GWAS data. We determined via simulations that scDRS is well-calibrated and powerful in identifying individual cells associated to disease. We applied scDRS to GWAS data from 74 diseases and complex traits (average N =346K) in conjunction with 16 scRNA-seq data sets spanning 1.3 million cells from 31 tissues and organs. At the cell type level, scDRS broadly recapitulated known links between classical cell types and disease, and also produced novel biologically plausible findings. At the individual cell level, scDRS identified subpopulations of disease-associated cells that are not captured by existing cell type labels, including subpopulations of CD4+ T cells associated with inflammatory bowel disease, partially characterized by their effector-like states; subpopulations of hippocampal CA1 pyramidal neurons associated with schizophrenia, partially characterized by their spatial location at the proximal part of the hippocampal CA1 region; and subpopulations of hepatocytes associated with triglyceride levels, partially characterized by their higher ploidy levels. At the gene level, we determined that genes whose expression across individual cells was correlated with the scDRS score (thus reflecting co-expression with GWAS disease genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.

bioinformatics↗

bioRxiv2021

White matter microstructure shows sex differences in late childhood: Evidence from 6,797 children

Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging (dMRI) approaches. However, sex differences in white matter microstructure prior to adulthood remain poorly understood; previous developmental work focused on conventional microstructure metrics and yielded mixed results. Here we rigorously characterized sex differences in white matter microstructure among over 6,000 children from the Adolescent Brain Cognitive Development (ABCD) Study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model - diffusion tensor imaging (DTI) - and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. Sex differences in FA were regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.

neuroscience↗

bioRxiv2020

Full-length transcript sequencing of human and mouse identifies widespread isoform diversity and alternative splicing in the cerebral cortex

Alternative splicing is a post-transcriptional regulatory mechanism producing multiple distinct mRNA molecules from a single pre-mRNA. Alternative splicing has a prominent role in the central nervous system, impacting neurodevelopment and various neuronal functions as well as being increasingly implicated in brain disorders including autism, schizophrenia and Alzheimers disease. Standard short-read RNA-Seq approaches only sequence fragments of the mRNA molecule, making it difficult to accurately characterize the true nature of RNA isoform diversity. In this study, we used long-read isoform sequencing (Iso-Seq) to generate full-length cDNA sequences and map transcript diversity in the human and mouse cerebral cortex. We identify widespread RNA isoform diversity amongst expressed genes in the cortex, including many novel transcripts not present in existing genome annotations. Alternative splicing events were found to make a major contribution to RNA isoform diversity in the cortex, with intron retention being a relatively common event associated with nonsense-mediated decay and reduced transcript expression. Of note, we found evidence for transcription from novel (unannotated genes) and fusion events between neighbouring genes. Although global patterns of RNA isoform diversity were found to be generally similar between human and mouse cortex, we identified some notable exceptions. We also identified striking developmental changes in transcript diversity, with differential transcript usage between human adult and fetal cerebral cortex. Finally, we found evidence for extensive isoform diversity in genes associated with autism, schizophrenia and Alzheimers disease. Our data confirm the importance of alternative splicing in the cerebral cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide this transcript level data as a resource to the scientific community.

genomics↗

bioRxiv2020

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

BackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection. MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring--an age comparable to mid adolescence in humans. ResultsWe identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes--PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring. ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

neuroscience↗

bioRxiv2017

A genome-wide association study for shared risk across major psychiatric disorders in a nation-wide birth cohort implicates fetal neurodevelopment as a key mediator

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here, we leverage the unique iPSYCH study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder SNP-heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during midgestation. This epoch is supported by partitioning cross-disorder SNP-heritability which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings indicate that dysregulation of genes that direct neurodevelopment by common genetic variants results in general liability for many later psychiatric outcomes.

genetics↗

bioRxiv2017

Discovery Of The First Genome-Wide Significant Risk Loci For ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks. These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population. Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci. The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits.

genetics↗