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Publications

Publications (71)
Article
Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we developed parallel RNA and DNA analysis after deep sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineage markers, identified from join...
Preprint
Full-text available
The recent advent of single cell RNA-sequencing and other high-throughput technologies has led to an explosion of cell type definitions across multiple organ systems. Consortia like the BRAIN Initiative Cell Census Network (BICCN) and the Human Cell Atlas (HCA) have begun to standardize and centralize the intake of data and associated metadata from...
Preprint
Full-text available
Background: Alu repeats contribute to phylogenetic novelties in conserved regulatory networks in primates. Exaptation of Alus in transcript isoforms could nucleate large-scale mRNA-miRNA interactions and modulate cellular outcomes. Result: Using a functional genomics approach, we report a transcript isoform of an orphan gene, CYP20A1 (CYP20A1_Alu-L...
Preprint
Full-text available
Single cell/nucleus RNA sequencing (scRNAseq) provides an unbiased transcriptomic profiling of individual cells, and is emerging as an essential tool to unravel the phenotypic heterogeneity of cells in complex biological systems. While computational methods for scRNAseq cell type clustering have advanced, the ability to integrate datasets to identi...
Preprint
Full-text available
Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we developed Parallel RNA and DNA analysis after Deep-sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineage markers, identified from join...
Preprint
Full-text available
The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an incr...
Preprint
Full-text available
The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolut...
Article
Full-text available
von Economo neurons (VENs) are bipolar, spindle-shaped neurons restricted to layer 5 of human frontoinsula and anterior cingulate cortex that appear to be selectively vulnerable to neuropsychiatric and neurodegenerative diseases, although little is known about other VEN cellular phenotypes. Single nucleus RNA-sequencing of frontoinsula layer 5 iden...
Preprint
Full-text available
Background: Primate-specific Alus contribute to transcriptional novelties in conserved gene regulatory networks. Alu RNAs are present at elevated levels in stress conditions and consequently leads to transcript isoform specific functional role modulating the physiological outcome. One of the possible mechanisms could be Alu nucleated mRNA-miRNA int...
Preprint
Full-text available
Background: Alu repeats contribute to phylogenetic novelties in conserved regulatory networks in primates. Exaptation of Alus in transcript isoforms could nucleate large-scale mRNA-miRNA interactions and modulate cellular outcomes. Result: Using a functional genomics approach, we report a transcript isoform of an orphan gene, CYP20A1 (CYP20A1_Alu-L...
Preprint
Full-text available
Autism is a highly heritable, complex disorder where de novo mutation (DNM) variation contributes significantly to disease risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare mutations. We report and replicate a transmission disequilibrium of private likely-gene disr...
Preprint
Full-text available
Single-cell technologies enable measure of unique cellular signatures, but are typically limited to a single modality. Computational approaches allow integration of diverse single-cell datasets, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of sing...
Article
Full-text available
Seeking new insights into the 顺心彩票ostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortica...
Article
Full-text available
While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ~8,825 sequenced parent-child trios (n ~26,475 individuals) and identify 54 genes with a DNM enrichment in males...
Article
Full-text available
The mammalian neocortex is subdivided into a series of cortical areas that are functionally and anatomically distinct and are often distinguished in brain sections using histochemical stains and other markers of protein expression. We searched the Allen Mouse Brain Atlas, a database of gene expression, for novel markers of cortical areas. To screen...
Article
Full-text available
Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and in...
Article
Full-text available
The cerebral cortex constitutes more than half the volume of the human brain and is presumed to be responsible for the neuronal computations underlying complex phenomena, such as perception, thought, language, attention, episodic memory and voluntary movement. Rodent models are extremely valuable for the investigation of brain development, but cann...
Preprint
Full-text available
von Economo neurons (VENs) are bipolar, spindle-shaped neurons restricted to layer 5 of human frontoinsula and anterior cingulate cortex that appear to be selectively vulnerable to neuropsychiatric and neurodegenerative diseases, although little is known about other VEN cellular phenotypes. Single nucleus RNA-sequencing of frontoinsula layer 5 iden...
Preprint
Alu repeats contribute to lineage specific novelties in conserved transcriptional regulatory networks. We report for the first time the origin of a multi-miRNA human specific sponge through exaptation of 23 Alu repeats that forms a novel principal isoform of CYP20A1 gene with a 9kb 3 prime UTR. This 3 prime UTR, confirmed by RACE, is an outlier in...
Preprint
Full-text available
Myriad cell types comprise the human neocortex, but their roles in normal brain function and disease are largely unknown because few tools exist. To find enhancer elements useful for cell type-specific genetic tools, we examined chromatin accessibility in >2,800 high-quality single human neocortical nuclei. Accessible elements frequently are conser...
Preprint
Full-text available
The mammalian neocortex is subdivided into a series of ‘cortical areas’ that are functionally and anatomically distinct, and are often distinguished in brain sections using histochemical stains and other markers of protein expression. We searched the Allen Mouse Brain Atlas, a database of gene expression, for novel markers of cortical areas. We emp...
Preprint
Full-text available
Seeking new insights into intracortical neuromodulation, we have analyzed results from deep RNA-Seq analysis of 22,439 individual mouse neocortical neurons. With special interest in ways that cortical neurons may use paracrine neuropeptide (NP) signaling to modulate one anothers' synaptic and electrical function, we have concentrated on neocortical...
Article
Full-text available
We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10??) for DNM. Intersecting these results with copy number...
Article
Full-text available
Transcriptomic profiling of complex tissues by single-nucleus RNA-sequencing (snRNA-seq) affords some advantages over single-cell RNA-sequencing (scRNA-seq). snRNA-seq provides less biased cellular coverage, does not appear to suffer cell isolation-based transcriptional artifacts, and can be applied to archived frozen specimens. We used well-matche...
Data
Properties of 463 cells matched to nuclei. (A) Proportion of matched cells isolated from transgenic mouse lines that label different subsets of cortical neurons. Note that a small number of “virally labeled” cells (<5%) were FAC sorted from wild-type mice based on retrograde labeling by viral injections into various cortical and subcortical structu...
Data
Nuclear versus whole cell transcript dropouts and intron retention. (A) Gene detection violin plots for nuclei and cells at different sub-sampled read depths. Note that while gene detection does not fully saturate, 90% as many genes are detected with 1 million versus approximately 2.5 million (“All”) reads. (B) Rate of gene dropouts in nuclei versu...
Data
Nuclear and cell clusters are well matched based on marker gene expression. (A) Pairwise correlations between previously reported mouse VISp cell type clusters and nuclear and cell clusters using average cluster expression of the top shared marker genes. Heatmaps show remarkably similar correlation patterns, supporting the existence of a well match...
Data
Differentially expressed genes in cells versus nuclei using intronic plus exonic reads. (XLSX)
Data
Overview of single nucleus RNA-seq clustering pipeline. See methods for a detailed description of clustering steps. (TIFF)
Data
Nuclear proportion estimates are supported by multiple genes and consistent with previously reported values. (A) Box plots of log2-transformed expression of two nuclear transcripts, Meg3 and the small nucleolar RNA Snhg11, in matched nuclear and cell clusters. (B) Representative sections of VISp from three Cre-driver mouse lines with layer boundari...
Data
Average gene expression and detection in matched nuclei and cells. (XLSX)
Data
Differentially expressed genes in cells versus nuclei using only exonic reads. (XLSX)
Data
Cre-driver line composition of cell clusters. (XLSX)
Data
Gene ontology (GO) enrichment of differentially expressed genes in cells and nuclei based on intronic and exonic reads or only exonic reads. (XLSX)
Data
Gene properties including the number of clusters with any expression, maximum cluster expression (FPKM of exonic reads only), cell type marker score (beta), and estimated nuclear proportion of transcripts. (XLSX)
Article
Full-text available
The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133...
Article
Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single-cell/nucleus RNA sequencing revealed ubiquitous HC...
Preprint
Full-text available
This paper studies measurement linkage. An example from cell biology helps explain the problem: imagine for a given cell we can either sequence the cell's RNA or we can examine its morphology, but not both. Given a cell's morphology, what do we expect to see in its RNA? Given a cell's RNA, what do we expect in its morphology? More broadly, given a...
Article
Full-text available
We describe convergent evidence from transcriptomics, morphology, and physiology for a specialized GABAergic neuron subtype in human cortex. Using unbiased single-nucleus RNA sequencing, we identify ten GABAergic interneuron subtypes with combinatorial gene signatures in human cortical layer 1 and characterize a group of human interneurons with ana...
Preprint
Full-text available
Elucidating the cellular architecture of the human neocortex is central to understanding our cognitive abilities and susceptibility to disease. Here we applied single nucleus RNA-sequencing to perform a comprehensive analysis of cell types in the middle temporal gyrus of human cerebral cortex. We identify a highly diverse set of excitatory and inhi...
Article
Full-text available
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia m...
Preprint
Full-text available
Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single cell/nucleus RNA sequencing revealed ubiquitous HC...
Article
Full-text available
Cells are fundamental function units of multicellular organisms, with different cell types playing distinct physiological roles in the body. The recent advent of single cell transcriptional profiling using RNA sequencing is producing "big data", enabling the identification of novel human cell types at an unprecedented rate. In this review, we summa...
Article
Full-text available
Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single- cell/nucleus RNA sequencing revealed ubiquitous H...
Preprint
Full-text available
With few exceptions, the marked advances in knowledge about the genetic basis for schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map...
Article
Full-text available
Background: A fundamental characteristic of multicellular organisms is the specialization of functional cell types through the process of differentiation. These specialized cell types not only characterize the normal functioning of different organs and tissues, they can also be used as cellular biomarkers of a variety of different disease states a...
Article
Full-text available
GABAergic interneurons are essential for neural circuit function, and their loss or dysfunction is implicated in human neuropsychiatric disease. In vitro methods for interneuron generation hold promise for studying human cellular and functional properties and, ultimately, for therapeutic cell replacement. Here we describe a protocol for generating...
Conference Paper
Next generation sequencing of the RNA content of single cells or single nuclei (sc/nRNA-seq) has become a powerful approach to understand the cellular complexity and diversity of multicellular organisms and environmental ecosystems. However, the fact that the procedure begins with a relatively small amount of starting material, thereby pushing the...
Article
Full-text available
The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division...
Article
Full-text available
Developmental changes in the temporal and spatial regulation of gene expression drive the emergence of normal mature brain function, while disruptions in these processes underlie many neurodevelopmental abnormalities. To solidify our foundational knowledge of such changes in a primate brain with an extended period of postnatal maturation like in hu...
Article
Full-text available
Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in spec...
Article
Full-text available
Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behav-iorally have met with limited success. Hypothesiz-ing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15...
Article
Full-text available
We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and populati...
Article
Full-text available
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the...
Article
Full-text available
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the...