Jay Shendure
Seattle
Genomics technology developer. Developmental biology adult learner. Professor at @uwgenome @HHMINEWS @BrotmanBaty SeaHub @AllenInstitute /him.
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Articles by Jay Shendure
SciPhy: A Bayesian phylogenetic framework using sequential genetic lineage tracing data
Abstract CRISPR-based lineage tracing offers a promising avenue to decipher single-cell lineage trees, especially in organisms not amenable to microscopy. Sequential genome editing records not only genetic edits but also the order in which they occur. To leverage this enriched information, we introduce SciPhy, a simulation and inference tool implemented in BEAST 2. SciPhy utilizes a Bayesian phylogenetic approach to jointly estimate time-scaled phylogenies and cell population parameters.
Pool-packaged AAV libraries exhibit extensive length-dependent and homology-dependent chimerism
Abstract Adeno-associated viruses (AAVs) are preferred gene therapy vectors because of their versatility, durability and safety profile. Here, we demonstrate extensive chimerism, manifesting as pervasive barcode swapping, among complex recombinant AAV (rAAV) libraries that are packaged as a pool. The observed chimerism is length and homology dependent but capsid independent, in some cases affecting the majority of packaged rAAV genomes.
Technical and biological sources of noise confound multiplexed enhancer AAV screening
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Abstract Cis-acting regulatory enhancer elements are powerful tools for achieving cell type-specific genetic access in adeno-associated virus (AAV) delivery platforms. However, a significant bottleneck in enhancer discovery remains the accurate characterization of their in vivo expression patterns, which currently relies on labor-intensive, gold-standard one-by-one validation.
By Avery C. Hunker, John K. Mich, Naz Taskin, Amy Torkelson, Trangthanh Cardenas, Jean-Benoît Lalanne, Joseph Mahoney, Darren Bertagnolli, Anish Bhaswanth Chakka, Rushil Chakrabarty, Nicholas Donadio, Rebecca A Ferrer, Molly J Gasperini, Jeff Goldy, Junitta B. Guzman, Kelly Jin, Shannon Khem, Rana Kutsal, Refugio Martinez, Dakota Newman, Nick Pena, Christine Rimorin, Dana Rocha, Nadiya Shapovalova, Michael Tieu, Natalie Weed, Thomas Zhou, Rebecca A Hodge, Shenqin Yao, Jay Shendure, Kimberly Smith, Ed Lein, Bosiljka Tasic, Boaz P. Levi, Jonathan T. Ting
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Nature
Verified
The proteomic landscape and temporal dynamics of human and mouse gastruloid development
Abstract The embryo establishes a body plan and primes itself for organogenesis during gastrulation. As gastrulation is challenging to study in vivo, stem-cell-derived ‘gastruloids’ have emerged as powerful surrogates. Although transcriptomics and imaging have been applied extensively to such embryo models, the dynamics of their proteomes remains largely unknown. Here we apply quantitative proteomics to human and mouse gastruloids at four key stages.
Remembrance of inflammations past
NEWS AND VIEWS 25 March 2026 Chronic inflammation increases the risk of colon cancer. This inflammation drives epigenetic changes in the nucleus of stem cells that promote tumour formation. A condition involving chronic inflammation of the colon, called ulcerative colitis, is associated with an increased risk of developing colorectal cancer1. Moreover, this risk correlates with the cumulative effect of inflammatory episodes rather than the extent of active inflammation at the time of diagnosis2.
A multiplex, prime editing framework for identifying drug resistance variants at scale
Osimertinib is the current standard therapy for non-small cell lung cancer patients harboring an EGFR T790M mutation. However, resistance to osimertinib typically develops, on average, within 10 months of treatment due to histological transformation or the acquisition of oncogene amplifications or other resistance mutations.41 Because of this, newer fourth-generation TKIs have been developed to treat osimertinib-resistant non-small cell lung cancers.
Multichannel genomic recording of biological information with ENGRAM - Nature Protocols
Abstract Molecular recording is an emerging paradigm for measuring biology over time. Enhancer-mediated genomic recording of activity in multiplex (ENGRAM) is a recently described synthetic biology circuit architecture that converts the transient activity of cis-regulatory elements (CREs) into stable genomic records that can be retrospectively recovered via DNA sequencing. Here we provide a step-by-step protocol for conducting ENGRAM experiments and analyzing the resulting data.
Multicondition and multimodal temporal profile inference during mouse embryonic development
3,10 1Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; 2eScience Institute, University of Washington, Seattle, Washington 98195, USA; 3Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98195, USA; 4Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, Washington 98195, USA; 5Howard Hughes Medical Institute, Seattle, Washington 98195, USA; 6Allen Discovery Center for Cell Lineage...
Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks - Nature Genetics
Abstract Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4+ T cells.
Combinatorial mapping of E3 ubiquitin ligases to their target substrates
Results We sought to develop a high-throughput method for screening combinatorial libraries of E3 perturbations and potential substrates. To this end, we adopted a GPS-inspired dual-fluorescent reporter9 expressing a GFP-fusion protein, which represents the putative ligase substrate, and an mCherry reporter translated from an internal ribosome entry site (IRES) (Figure 1A). Expression of the GFP-IRES-mCherry is controlled by the doxycycline-inducible tetracycline response element (TRE).
Massively parallel characterization of transcriptional regulatory elements - Nature
Abstract The human genome contains millions of candidate cis-regulatory elements (cCREs) with cell-type-specific activities that shape both health and many disease states1.
How to build the virtual cell with artificial intelligence: Priorities and opportunities
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Keywords cell biology AI ML virtual cell Introduction The cell, the fundamental unit of life, is a wondrously intricate entity with properties and behaviors that challenge the limits of physical and computational modeling. Every cell is a dynamic and adaptive system in which complex behavior emerges from a myriad of molecular interactions. Some aspects are remarkably robust to perturbations, such as the elimination of genes or their replacement with homologs from different species.
By Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Mohammed AlQuraishi, Patricia A. Brennan, Daniel B. Burkhardt, Andrea Califano, Jonah Cool, Abby Dernburg, Amy E. Herr, Eric J Horvitz, Patrick D. Hsu, Viren Jain, Gregory Johnson, Thomas Kalil, David Kelley, Shana O. Kelley, Anna Kreshuk, Tim Mitchison, Stephani Otte, Jay Shendure, Nicholas J Sofroniew, Fabian J. Theis, Christina V. Theodoris, Srigokul Upadhyayula, Bo Wang, Eric Xing, Serena Yeung-Levy, Marinka Zitnik, Theofanis Karaletsos, Aviv Regev, Emma Lundberg, Jure Leskovec, Stephen R. Quake, Marcel Roed, Theo Alexandrov, Kirsty Ewing, Matthias Haury, Marc Valer
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Cell Press
Verified
The lives of cells, recorded
Abstract A paradigm for biology is emerging in which cells can be genetically programmed to write their histories into their own genomes. These records can subsequently be read, and the cellular histories reconstructed, which for each cell could include a record of its lineage relationships, extrinsic influences, internal states and physical locations, over time. DNA recording has the potential to transform the way that we study developmental and disease processes.
Efficient and highly amplified imaging of nucleic acid targets in cellular and histopathological samples with pSABER - Nature Methods
Abstract In situ hybridization (ISH) is a powerful tool for investigating the spatial arrangement of nucleic acid targets in fixed samples. ISH is typically visualized using fluorophores to allow high sensitivity and multiplexing or with colorimetric labels to facilitate covisualization with histopathological stains. Both approaches benefit from signal amplification, which makes target detection effective, rapid and compatible with a broad range of optical systems.
Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart - Communications Biology
Abstract Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors.
Molecular recording using DNA Typewriter - Nature Protocols
Abstract Recording molecular information to genomic DNA is a powerful means of investigating topics ranging from multicellular development to cancer evolution. With molecular recording based on genome editing, events such as cell divisions and signaling pathway activity drive specific alterations in a cell’s DNA, marking the genome with information about a cell’s history that can be read out after the fact.
Impacts of human mobility on the citywide transmission dynamics of 18 respiratory viruses in pre- and post-COVID-19 pandemic years - Nature Communications
Abstract Many studies have used mobile device location data to model SARS-CoV-2 dynamics, yet relationships between mobility behavior and endemic respiratory pathogens are less understood. We studied the effects of population mobility on the transmission of 17 endemic viruses and SARS-CoV-2 in Seattle over a 4-year period, 2018-2022. Before 2020, visits to schools and daycares, within-city mixing, and visitor inflow preceded or coincided with seasonal outbreaks of endemic viruses.
Multi-condition and multi-modal temporal profile inference during mouse embryonic development
Abstract The emergence of single-cell time-series datasets enables modeling of changes in various types of cellular profiles over time. However, due to the disruptive nature of single-cell measurements, it is impossible to capture the full temporal trajectory of a particular cell. Furthermore, single-cell profiles can be collected at mismatched time points across different conditions (e.g., sex, batch, disease) and data modalities (e.g., scRNA-seq, scATAC-seq), which makes modeling challenging.
Embryo-scale reverse genetics at single-cell resolution - Nature
Abstract The maturation of single-cell transcriptomic technologies has facilitated the generation of comprehensive cellular atlases from whole embryos1,2,3,4. A majority of these data, however, has been collected from wild-type embryos without an appreciation for the latent variation that is present in development.
Single-cell, whole-embryo phenotyping of mammalian developmental disorders - Nature
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Abstract Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models.
By Chengxiang Qiu, Oana Amarie, Rose Yinghan Behncke, Diane E. Dickel, Madeleine Duran, Helmut Fuchs, Valerie Gailus-Durner, Sudha Rajderkar, Michael Robson, Lauren Saunders, Yiwen Zhu, Vera M. Kalscheuer, Daniel M. Ibrahim, Ingo Kurth, Axel Visel, Len A. Pennacchio, Cole Trapnell, Junyue Cao, Jay Shendure, Nils Hansmeier, Uwe Kornak
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Nature
Verified
Publisher Correction: Pluripotent stem cell-derived model of the post-implantation human embryo - Nature
Correction to: Nature https://doi.org/10.1038/s41586-023-06368-y Published online 27 June 2023 In the version of this article initially published, ref. 18 (Simunovic, M. et al., Cell Stem Cell. https://doi.org/10.1016/j.stem.2022.05.001 (2022)) was missing, and in Fig. 1a,b, yellow header labels for “GATA6” and “GATA3” were missing.
Pluripotent stem cell-derived model of the post-implantation human embryo - Nature
Abstract The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Models of the embryo derived from stem cells are important tools for interrogating developmental events and tissue–tissue crosstalk during these stages1. Here we establish a model of the human post-implantation embryo, a human embryoid, comprising embryonic and extraembryonic tissues.
A reference cell tree will serve science better than a reference cell atlas
Summary Single-cell biology is facing a crisis of sorts. Vast numbers of single-cell molecular profiles are being generated, clustered and annotated. However, this is overwhelmingly ad hoc, and we continue to lack a principled, unified, and well-moored system for defining, naming, and organizing cell types. In this perspective, we argue against an atlas or periodic table-like discretization as the right metaphor for a reference taxonomy of cell types.
Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment - Nature Neuroscience
Abstract Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques.
Embryo model completes gastrulation to neurulation and organogenesis - Nature
Abstract Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro1,2,3,4,5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6,7,8,9,10,11.
DNA Typewriter Taps Out a Record Inside Cells
While developing a new system for recording within cells, geneticist Jay Shendure and his team decided to give it a test run by using it to encode text. Since their invention relied on a nearly brand-new recording medium, DNA, they wanted to use messages that evoked a sense of historical significance.
A time-resolved, multi-symbol molecular recorder via sequential genome editing - Nature
Abstract DNA is naturally well suited to serve as a digital medium for in vivo molecular recording. However, contemporary DNA-based memory devices are constrained in terms of the number of distinct ‘symbols’ that can be concurrently recorded and/or by a failure to capture the order in which events occur1. Here we describe DNA Typewriter, a general system for in vivo molecular recording that overcomes these and other limitations.
Tethering distinct molecular profiles of single cells by their lineage histories to investigate sources of cell state heterogeneity
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A hybrid open-top light-sheet microscope for versatile multi-scale imaging of cleared tissues - Nature Methods
Abstract Light-sheet microscopy has emerged as the preferred means for high-throughput volumetric imaging of cleared tissues. However, there is a need for a flexible system that can address imaging applications with varied requirements in terms of resolution, sample size, tissue-clearing protocol, and transparent sample-holder material.
Precise genomic deletions using paired prime editing - Nature Biotechnology
Abstract Current methods to delete genomic sequences are based on clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 and pairs of single-guide RNAs (sgRNAs), but can be inefficient and imprecise, with errors including small indels as well as unintended large deletions and more complex rearrangements.
A continuous model of early mammalian development
During embryonic development, new cell types emerge with stunning speed and robustness. The process of gastrulation — in which a single layer of cells gives rise to multiple ‘germ layers’ — is fundamental to the early development of most animals. Although studied for more than 150 years, many aspects of gastrulation remain elusive, not least a comprehensive understanding of the molecular factors governing the specification of the many cell lineages that emerge from this process.
CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores
Abstract Background Splicing of genomic exons into mRNAs is a critical prerequisite for the accurate synthesis of human proteins. Genetic variants impacting splicing underlie a substantial proportion of genetic disease, but are challenging to identify beyond those occurring at donor and acceptor dinucleotides. To address this, various methods aim to predict variant effects on splicing.
Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome
Abstract Firre encodes a lncRNA involved in nuclear organization. Here, we show that Firre RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of the Polycomb repressive complexes.
20th Anniversary
October 2020 marks the 20th anniversary of the launch of Nature Reviews Genetics. To celebrate this milestone, we have delved into our archives to curate a Collection of cutting-edge articles, historical pieces and thought-provoking commentaries and opinions. Featuring a range of article types, including Reviews, Perspectives, Viewpoints and Comments, this Collection provides a glimpse of the genetics and genomics field over the past two decades.
Predicting mRNA Abundance Directly from Genomic Sequence Using Deep Convolutional Neural Networks
Highlights • Deep neural networks strongly predict gene expression levels solely from DNA sequence • Models help infer transcriptional and post-transcriptional gene regulatory mechanisms • Predictive power is competitive with models using thousands of biochemical datasets • CpG dinucleotide content at core promoters is strongly predictive of mRNA abundance Summary Algorithms that accurately predict gene structure from primary sequence alone were transformative for annotating the human genome.
Sci-fate characterizes the dynamics of gene expression in single cells
Abstract Gene expression programs change over time, differentiation and development, and in response to stimuli. However, nearly all techniques for profiling gene expression in single cells do not directly capture transcriptional dynamics.
Towards a comprehensive catalogue of validated and target-linked human enhancers - Nature Reviews Genetics
Abstract The human gene catalogue is essentially complete, but we lack an equivalently vetted inventory of bona fide human enhancers. Hundreds of thousands of candidate enhancers have been nominated via biochemical annotations; however, only a handful of these have been validated and confidently linked to their target genes. Here we review emerging technologies for discovering, characterizing and validating human enhancers at scale.
MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect
Daniel Esposito1 na1, Jochen Weile2,3,4,5 na1, Jay Shendure6,7,8, Lea M. Starita6,7, Anthony T. Papenfuss1,9,10,11,12, Frederick P. Roth2,3,4,5,13, Douglas M. Fowler6,13,14 & Alan F.
Mechanisms of Interplay between Transcription Factors and the 3D Genome
Alberti S. Phase separation in biology. Curr. Biol. 2017; 27: R1097-R1102 Alekseyenko A.A. Gorchakov A.A. Zee B.M. Fuchs S.M. Kharchenko P.V. Kuroda M.I. Heterochromatin-associated interactions of Drosophila HP1a with dADD1, HIPP1, and repetitive RNAs. Genes Dev. 2014; 28: 1445-1460 Allen B.L. Taatjes D.J. The Mediator complex: a central integrator of transcription. Nat. Rev. Mol. Cell Biol. 2015; 16: 155-166 Apostolou E. Thanos D.
Supervised classification enables rapid annotation of cell atlases
Abstract Single-cell molecular profiling technologies are gaining rapid traction, but the manual process by which resulting cell types are typically annotated is labor intensive and rate-limiting. We describe Garnett, a tool for rapidly annotating cell types in single-cell transcriptional profiling and single-cell chromatin accessibility datasets, based on an interpretable, hierarchical markup language of cell type-specific genes.
A pooled single-cell genetic screen identifies regulatory checkpoints in the continuum of the epithelial-to-mesenchymal transition
Abstract Integrating single-cell trajectory analysis with pooled genetic screening could reveal the genetic architecture that guides cellular decisions in development and disease. We applied this paradigm to probe the genetic circuitry that controls epithelial-to-mesenchymal transition (EMT). We used single-cell RNA sequencing to profile epithelial cells undergoing a spontaneous spatially determined EMT in the presence or absence of transforming growth factor-β.
Concurrent Genome and Epigenome Editing by CRISPR-Mediated Sequence Replacement
Abstract Recent advances in genome editing have facilitated the direct manipulation of not only the genome, but also the epigenome. Genome editing is typically performed by introducing a single CRISPR/Cas9-mediated double stranded break (DSB), followed by NHEJ or HDR mediated repair. Epigenome editing, and in particular methylation of CpG dinucleotides, can be performed using catalytically inactive Cas9 (dCas) fused to a methyltransferase domain.
Expanding the single-cell genomics toolkit
Epigenetic heterogeneity underlies the diversity of cell states found in health and disease. A new study presents a method for profiling of histone modifications in single cells and applies it to identify rare chromatin states, possibly predisposed to drug resistance, within patient-derived tumor xenografts. Access optionsAccess options Subscribe to Journal Get full journal access for 1 year $225.00 only $18.75 per issue All prices are NET prices. VAT will be added later in the checkout.
Publisher Correction: DNA sequencing at 40: past, present and future
Correction to: Nature https://doi.org/10.1038/nature24286, published online 11 October 2017. In this Review, the year of publication of reference 54 should be 2005, not 2015. In Box 2, “1982: GenBank (https://www.ncbi.nlm.nih.gov/genbank/statistics/)” should read “1982: Genbank/ENA/DDBJ” and “2007: NCBI Short Read Archive” should read “2007: NCBI and ENA Short Read Archives”; this is because the launches of these American, European and Japanese databases were coordinated.
Genomic Medicine-Progress, Pitfalls, and Promise
Bailey M.H. Tokheim C. Porta-Pardo E. Sengupta S. Bertrand D. Weerasinghe A. Colaprico A. Wendl M.C. Kim J. Reardon B. et al. MC3 Working Group Cancer Genome Atlas Research Network Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell. 2018; 173: 371-385.e18 Baird P.A. Anderson T.W. Newcombe H.B. Lowry R.B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 1988; 42: 677-693 Bernier R. Golzio C. Xiong B. Stessman H.A. Coe B.P. Penn O. Witherspoon K. Gerdts J.
High Sensitivity Profiling of Chromatin Structure by MNase-SSP
Highlights • MNase-SSP decreases sequence bias and increases short DNA fragment representation • MNase-SSP captures subnucleosomal architecture and maps minimally protected fragments • Ctcf-bound short fragments distinguish different transcription factor binding modes Summary A complete view of eukaryotic gene regulation requires that we accurately delineate how transcription factors (TFs) and nucleosomes are arranged along linear DNA in a sensitive, unbiased manner.
Supervised classification enables rapid annotation of cell atlases
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How two 1990s discoveries have led to (some) cured cancers, and a Nobel Prize
This year’s award of the Nobel Prize for Physiology and Medicine to James P. Allison and Tasuku Honjo, for their work in the early 1990s on immune checkpoint proteins CTLA4 and PD1, is a fitting recognition of how their work has led to a seismic shift in the way we treat cancer. In a remarkably short time, drugs that inhibit these immune checkpoints (or immune brakes) have transformed the practice of clinical oncology.
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