Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages

Cell stem cell, Год журнала: 2023, Номер 30(3), С. 312 - 332.e13

Опубликована: Фев. 15, 2023

Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular cellular mechanisms will require scalable approaches. Here, we describe a "cell village" experimental platform used analyze genetic, molecular, phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured shared vitro environment using algorithms (Dropulation Census-seq) assign phenotypes individual donors. Through rapid induction of stem cell-derived cells, measurements natural genetic variation, CRISPR-Cas9 perturbations, identified common variant that regulates antiviral IFITM3 expression explains most inter-individual susceptibility Zika virus. We also detected QTLs corresponding GWAS loci for brain traits discovered novel disease-relevant regulators proliferation differentiation such as CACHD1. This approach provides ways elucidate effects genes on phenotypes.

Язык: Английский

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Relating enhancer genetic variation across mammals to complex phenotypes using machine learning

Science, Год журнала: 2023, Номер 380(6643)

Опубликована: Апрель 27, 2023

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent functionally conserved despite low sequence conservation. We developed Tissue-Aware Conservation Inference Toolkit (TACIT) associate candidate with species' using predictions from machine learning models trained on specific tissues. Applying TACIT motor cortex parvalbumin-positive interneuron neurological revealed dozens enhancer-phenotype associations, including brain size-associated interact genes implicated in microcephaly or macrocephaly. provides a foundation for identifying associated evolution any convergently evolved phenotype large group aligned genomes.

Язык: Английский

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Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) examine cell composition transcriptomics, identifying dysregulation of type-specific gene regulatory networks (GRNs) autism spectrum disorder (ASD), which we corroborated using assay for transposase-accessible chromatin with (snATAC-seq) spatial transcriptomics. Transcriptomic were primarily type specific, involving multiple types, most prominently interhemispheric callosal-projecting neurons, interneurons within superficial laminae, distinct glial reactive states oligodendrocytes, microglia, astrocytes. Autism-associated GRN drivers their targets enriched rare common risk variants, connecting cellular circuit alterations the human brain.

Язык: Английский

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Neural heterogeneity controls computations in spiking neural networks

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(3)

Опубликована: Янв. 10, 2024

The brain is composed of complex networks interacting neurons that express considerable heterogeneity in their physiology and spiking characteristics. How does this neural influence macroscopic dynamics, how might it contribute to computation? In work, we use a mean-field model investigate computation heterogeneous networks, by studying the cell thresholds affects three key computational functions population: gating, encoding, decoding signals. Our results suggest serves different types. inhibitory interneurons, varying degree spike threshold allows them gate propagation signals reciprocally coupled excitatory population. Whereas homogeneous interneurons impose synchronized dynamics narrow dynamic repertoire neurons, act as an offset while preserving neuron function. Spike also controls entrainment properties periodic input, thus affecting temporal gating synaptic inputs. Among increases dimensionality improving network’s capacity perform tasks. Conversely, suffer for function generation, but excel at encoding via multistable regimes. Drawing from these findings, propose intra-cell-type mechanism sculpting local circuits permitting same canonical microcircuit be tuned diverse

Язык: Английский

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Astrocyte-secreted neurocan controls inhibitory synapse formation and function

Neuron, Год журнала: 2024, Номер 112(10), С. 1657 - 1675.e10

Опубликована: Апрель 3, 2024

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an protein. After secretion from astrocytes, is cleaved into N- C-terminal fragments. We found these fragments have distinct localizations in extracellular matrix. The fragment localizes to controls cortical function. Neurocan knockout mice lacking whole protein or only its domain reduced numbers Through super-resolution microscopy, vivo proximity labeling TurboID, astrocyte-specific rescue approaches, discovered somatostatin-positive regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific mammalian brain.

Язык: Английский

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