Cited by 209Single-cell and spatial transcriptomicsNeurogenesis and neuroplasticity mechanismsPrimate Behavior and Ecology

Comparative transcriptomics reveals human-specific cortical features

Open access
Jorstad, Nikolas L., Song, Janet H. T., Exposito-Alonso, David, Suresh, Hamsini, Castro-Pacheco, Nathan, Krienen, Fenna M., Yanny, Anna Marie, Close, Jennie +36 more·2023·Science

Published version of a preprint

Abstract

Abstract Humans have unique cognitive abilities among primates, including language, but their molecular, cellular, and circuit substrates are poorly understood. We used comparative single nucleus transcriptomics in adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets from the middle temporal gyrus (MTG) to understand human-specific features of cellular and molecular organization. Human, chimpanzee, and gorilla MTG showed highly similar cell type composition and laminar organization, and a large shift in proportions of deep layer intratelencephalic-projecting neurons compared to macaque and marmoset. Species differences in gene expression generally mirrored evolutionary distance and were seen in all cell types, although chimpanzees were more similar to gorillas than humans, consistent with faster divergence along the human lineage. Microglia, astrocytes, and oligodendrocytes showed accelerated gene expression changes compared to neurons or oligodendrocyte precursor cells, indicating either relaxed evolutionary constraints or positive selection in these cell types. Only a few hundred genes showed human-specific patterning in all or specific cell types, and were significantly enriched near human accelerated regions (HARs) and conserved deletions (hCONDELS) and in cell adhesion and intercellular signaling pathways. These results suggest that relatively few cellular and molecular changes uniquely define adult human cortical structure, particularly by affecting circuit connectivity and glial cell function.

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Crossref · 10.1126/science.ade9516

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  • BICCN and BICAN reference classifications provide a foundational reference to understand the cellular, molecular and epigenomic underpinnings of AD.

    “These reference classifications provide an extremely powerful foundational reference to understand the cellular, molecular and epigenomic underpinnings of AD.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [18]

    The Within-species cell type taxonomies section describes cortical cell-type classifications, and the Discussion says the data are a resource for future investigation of disease-associated gene programs. The paper does not specifically establish these classifications as a reference for understanding Alzheimer’s disease or its epigenomic underpinnings. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • The study profiled 3.4 million high-quality nuclei across all modalities, mapping each to one of 139 molecular cell types from an expanded BRAIN Initiative MTG cellular taxonomy that included disease-associated states.

    “We collectively profiled 3.4 million high-quality nuclei across all modalities, mapping each to one of 139 molecular cell types from an expanded BRAIN Initiative MTG cellular taxonomy18 that included disease-associated states.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [18]

    The Within-species cell type taxonomies section describes an expanded human MTG taxonomy, supporting the citation’s identification of a taxonomy. It reports 151 human clusters, not 139 molecular cell types, and does not describe disease-associated states. The 3.4 million nuclei are presented as the citing authors’ own profiling, not a result attributed to this source. (LLM, conf=0.87)

    Experimental — accuracy not yet measured
  • Brains were collected using highly optimized brain preparation methods with a mean postmortem interval of 7.0 h that enable exceptionally high-quality snRNA-seq, snATAC-seq and MERFISH profiling.

    “Brains were collected using highly optimized brain preparation methods (mean postmortem interval = 7.0 h; Extended Data Fig. 1b) that enable exceptionally high-quality snRNA-seq, snATAC–seq and MERFISH profiling17–19,23,36,37.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [18]

    The Methods sections on tissue specimens, single-nucleus RNA sequencing, and in situ gene-expression profiling describe preparation of postmortem human brain tissue for snRNA-seq and MERFISH; page numbers are unavailable in our copy. They do not report a mean postmortem interval of 7.0 hours or establish that these methods enabled snATAC-seq profiling. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • In MTG snRNA-seq data, NPAS3 is differentially expressed in several neuronal types when comparing human and chimpanzee samples.

    “In this dataset, we found that NPAS3 is differentially expressed in several neuronal types when comparing human and chimpanzee samples (Jorstad et al. 2023).”
  • Both Oligo_2 and Oligo_4 supertypes are found throughout the cortical column in the BRAIN Initiative reference dataset.

    “both supertypes are found throughout the cortical column in the BRAIN Initiative reference dataset18.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [18]

    The Within-species cell type taxonomies section describes oligodendrocytes and says that human MTG cell-type distributions were summarized by cortical depth. The passages found by searching for Oligo_2, Oligo_4, and the BRAIN Initiative reference dataset do not identify those supertypes or say that both occur throughout the cortical column. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 3

  1. [22]Krienen FM, Levandowski KM, Zaniewski H, del Rosario RCH, Schroeder ME, Goldman M, Lutservitz A, Zhang Q, Li KX, Beja-Glasser VF, Sharma J, Shin TW, Mauermann A, Wysoker A, Nemesh J, Kashin S, Vergara J, Chelini G, Dimidschstein J, Berretta S, Boyden E, McCarroll SA, Feng G, A marmoset brain cell census reveals persistent influence of developmental origin on neurons. bioRxiv (2022), p. 2022.10.18.512442.
  2. [33]Fang R, Xia C, Close JL, Zhang M, He J, Huang Z, Halpern AR, Long B, Miller JA, Lein ES, Zhuang X, Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH. Science. 377, 56– 62 (2022). 35771910 PMC9262715
  3. [79]Paxinos G, Watson C, Petrides M, Rosa M, Tokuno H, The Marmoset Brain in Stereotaxic Coordinates (Elsevier Science, 2011).

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Authors
Jorstad, N. L., Song, J. H. T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F. M., Yanny, A. M., Close, J., Gelfand, E., Long, B., Seeman, S. C., Travaglini, K. J., Basu, S., Beaudin, M., Bertagnolli, D., Crow, M., Ding, S.-L., Eggermont, J., Glandon, A., Goldy, J., Kiick, K., Kroes, T., McMillen, D., Pham, T., Rimorin, C., Siletti, K., Somasundaram, S., Tieu, M., Torkelson, A., Feng, G., Hopkins, W. D., Höllt, T., Keene, C. D., Linnarsson, S., McCarroll, S. A., Lelieveldt, B. P., Sherwood, C. C., Smith, K., Walsh, C. A., Dobin, A., Gillis, J., Lein, E. S., Hodge, R. D., & Bakken, T. E.
Affiliations
  • Allen Institute for Brain Science (US)
  • Boston Children's Hospital (US)
  • Cold Spring Harbor Laboratory (US)
  • Harvard University (US)
  • Leiden University Medical Center (NL)
  • Karolinska Institutet (SE)
  • Broad Institute (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • Delft University of Technology (NL)
  • University of Washington (US)
  • George Washington University (US)
  • University of Toronto (CA)
Corresponding author
  • Jorstad, Nikolas L.
  • Song, Janet H. T.
  • Exposito-Alonso, David
  • Hodge, Rebecca D.
  • Bakken, Trygve E.
Venue
Science
Published
2023-10-13
Volume
382
Issue
6667
Pages
eade9516-eade9516
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W4387595270
Cited by
208
References
89
Citations by year
2026: 58 · 2025: 77 · 2024: 57 · 2023: 15 · 2022: 1
FWCI
18.48
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Research Repository (Delft University of Technology) (submittedVersion)
Funders
  • National Science Foundation (NS092988, U01MH114819, 2021785)
  • Nancy and Buster Alvord Endowment
  • National Alliance for Research on Schizophrenia and Depression
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.004.012, 17126, BRAINSCAPES 024.004.012)
  • National Institutes of Health (5u01mh114812-03, 1f32mh114501-01, EF-2021785, U01MH114812)
  • Genentech
  • National Institute of Mental Health (U19MH114821, U01MH114812, U01MH114819, R01MH113005, F32-MH114501, U19MH114830)
  • National Human Genome Research Institute (R01HG011641, R01HG009318)
  • National Institute of Neurological Disorders and Stroke (R24NS092988)
  • U.S. National Library of Medicine (R01LM012736)
  • Division of Emerging Frontiers
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Social Sciences › Psychology › Social Psychology › Primate Behavior and Ecology
Keywords
middle temporal gyrus, neocortex evolution, single-nucleus transcriptomics, cell type composition, laminar organization, deep-layer neurons, microglia, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, chimpanzees, gorillas, rhesus monkeys, marmoset, primate brain evolution
MeSH terms
Animals, Pan troglodytes, Cognition, Gorilla gorilla, Humans, Macaca mulatta, Phylogeny, Species Specificity, Temporal Lobe, Hominidae, Neocortex, Gene Expression Profiling, Transcriptome

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