Publications

2026

1. 

   Mesoscale molecular architecture of the human striatum across cell types and lifespan

   Andrew W. Kraft, Matthew Lee, Nirmala Rayan, and 7 more authors

   bioRxiv, 2026

   Posted March 6, 2026 (v2)

   Abstract PDF Data browser

   The human striatum coordinates a wide range of motor, cognitive, and affective functions, yet it has no obvious anatomical boundaries marking out functional subregions. Using Slide-tags spatial transcriptomics, the authors profiled roughly 1.1 million cells across the striatum from 19 postmortem donors and found a consistent division into six molecularly distinct zones, each defined by particular medium spiny neuron populations and coordinated neuron-astrocyte signaling. Dorsal zones showed relatively stronger expression of genes tied to synaptic remodeling and plasticity, while ventral zones were relatively enriched for semaphorin, chaperone, and hedgehog-pathway signaling. Extending these zonal definitions to a larger RNA-seq cohort of 131 donors, the authors found that dorsal zones undergo more age-related transcriptional change and that the molecular signature of zonation weakens with age overall. The work proposes a mesoscale molecular map of striatal anatomy that links cellular identity to functional specialization and vulnerability to aging.

2. 

   Inter-individual variation of cellular and gene-expression properties of the human striatum

   Steven Burger, Olivia Yoo, James Nemesh, and 34 more authors

   bioRxiv, 2026

   Posted March 20, 2026

   Abstract PDF Data browser

   Human brains differ from one person to the next in ways that likely shape behavior and disease risk, but the cellular and molecular basis of this variation is poorly understood. The authors analyzed cellular and gene-expression variation across the caudate, putamen, nucleus accumbens, internal capsule, and prefrontal cortex using single-nucleus RNA-seq of roughly 3.9 million nuclei from 178 adult donors. People with relatively more astrocytes in one brain region tended to have more astrocytes across all sampled regions, and the same coordinated pattern held for striatal interneurons, microglia, and oligodendrocyte precursor cells; OPC numbers also declined with age. Common genetic variants were found to influence expression levels of roughly ten thousand genes, with most of these effects specific to particular cell types. The dataset offers a resource for understanding how genetic and cellular variation across individuals relates to brain function and disease susceptibility.

2024

1. 

   Slide-tags enables single-nucleus barcoding for multimodal spatial genomics

   Andrew J. C. Russell, Jackson A. Weir, Naeem M. Nadaf, and 15 more authors

   Nature, 2024

   Abstract PDF

   Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are tagged with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions. These tagged nuclei can then be used as an input into a wide variety of single-nucleus profiling assays. Application of Slide-tags to the mouse hippocampus positioned nuclei at less than 10 μm spatial resolution and delivered whole-transcriptome data that are indistinguishable in quality from ordinary single-nucleus RNA-sequencing data. To demonstrate that Slide-tags can be applied to a wide variety of human tissues, we performed the assay on brain, tonsil and melanoma. We revealed cell-type-specific spatially varying gene expression across cortical layers and spatially contextualized receptor–ligand interactions driving B cell maturation in lymphoid tissue. A major benefit of Slide-tags is that it is easily adaptable to almost any single-cell measurement technology. As a proof of principle, we performed multiomic measurements of open chromatin, RNA and T cell receptor (TCR) sequences in the same cells from metastatic melanoma, identifying transcription factor motifs driving cancer cell state transitions in spatially distinct microenvironments. Slide-tags offers a universal platform for importing the compendium of established single-cell measurements into the spatial genomics repertoire.

2023

1. 

   Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender

   Stephen J. Fleming, Mark D. Chaffin, Alessandro Arduini, and 6 more authors

   Nature Methods, 2023

   Abstract PDF

   Droplet-based single-cell assays, including single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), generate considerable background noise counts, the hallmark of which is nonzero counts in cell-free droplets and off-target gene expression in unexpected cell types. Such systematic background noise can lead to batch effects and spurious differential gene expression results. Here we develop a deep generative model based on the phenomenology of noise generation in droplet-based assays. The proposed model accurately distinguishes cell-containing droplets from cell-free droplets, learns the background noise profile and provides noise-free quantification in an end-to-end fashion. We implement this approach in the scalable and robust open-source software package CellBender. Analysis of simulated data demonstrates that CellBender operates near the theoretically optimal denoising limit. Extensive evaluations using real datasets and experimental benchmarks highlight enhanced concordance between droplet-based single-cell data and established gene expression patterns, while the learned background noise profile provides evidence of degraded or uncaptured cell types.

2. 

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

   Michael F. Wells, James Nemesh, Sulagna Ghosh, and 24 more authors

   Cell Stem Cell, 2023

   Abstract PDF

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