A survey of human brain transcriptome diversity at the single cell level
Open accessAbstract
Significance: The brain comprises an immense number of cells and cellular connections. We describe the first, to our knowledge, single cell whole transcriptome analysis of human adult cortical samples. We have established an experimental and analytical framework with which the complexity of the human brain can be dissected on the single cell level. Using this approach, we were able to identify all major cell types of the brain and characterize subtypes of neuronal cells. We observed changes in neurons from early developmental to late differentiated stages in the adult. We found a subset of adult neurons which express major histocompatibility complex class I genes and thus are not immune privileged.
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The central nervous system of older mice is more complex than that of younger mice, making it harder to dissociate it into single cells, and as a result some cell types can get over- or underrepresented.
“The central nervous system of older mice is more complex than that of younger mice, making it harder to dissociate it into single cells, and as a result some cell types can get over-or underrepresented (Darmanis et al., 2015;Grindberg et al., 2013;Krishnaswami et al., 2016;Lake et al., 2016;Lake et al., 2017;Tasic et al., 2018).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Darmanis et al., 2015
The Materials and Methods section says that human brain tissue was dissociated into single-cell suspensions, but does not compare older and younger mice. The Abstract and Results discuss human developmental stages and differences between humans and mice, not age-related difficulty of dissociating mouse CNS tissue or resulting over- or underrepresentation of cell types. Searches for dissociation difficulty and cell-type sampling bias found no passage addressing the claim; page numbers were not available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredHi-C and single-cell sequencing had not been fully integrated at scale with brain genomics data.
“new methodologies, such as Hi-C and single-cell sequencing, have yet to be fully integrated at scale with brain genomics data (13–16).”
From Comprehensive functional genomic resource and integrative model for the human brain (2018) · cites this paper as [16]
Single-cell RNA-seq data from PsychENCODE and other brain studies were uniformly processed with standard pipelines.
“we used standard pipelines to uniformly process single-cell RNA-seq data from PsychENCODE, in conjunction with other single-cell studies on the brain (14, 16, 20).”
From Comprehensive functional genomic resource and integrative model for the human brain (2018) · cites this paper as [16]
Single-nucleus transcriptomes from multiple regions of human brain have established cell type taxonomies.
“Single-nucleus transcriptomes from multiple regions of the human brain have established cell type taxonomies (Fig. 2B–D) (Darmanis et al., 2015; Habib et al., 2017; Lake et al., 2016).”
From Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes (2021) · cites this paper as Darmanis et al., 2015
The number of cells for scRNA-seq and replicates for bulk RNA-seq were empirically determined based on previous studies, and the sample size allowed robust identification of cell populations as small as 20 cells.
“The number of cells for scRNA-seq and the number of replicates for bulk RNA-seq were empirically determined based on previous studies (Darmanis et al., 2015; Tabula Muris et al., 2018; Zhang et al., 2014). The used sample-size in scRNA-seq allowed us to robustly identify cell populations as small as 20 cells.”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Darmanis et al., 2015
Cellular heterogeneity in the human brain poses significant challenges for unraveling the gene regulatory architecture because the brain comprises heterogeneous cell populations with distinct gene expression and chromatin accessibility profiles.
“However, cellular heterogeneity poses significant challenges for unraveling the complexity in the gene regulatory architecture of the human brain, as it is comprised of heterogeneous cell populations, mostly different types of neurons and glia, each of which display distinct gene expression3,8–10 and chromatin accessibility profiles11–14.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [10]
NeuN+ and NeuN− FIRE-associated genes are mainly enriched in neurons and glia, respectively.
“As expected, NeuN+ and NeuN− FIRE-associated genes were mainly enriched in neurons and glia, respectively (Fig. 1i, j).”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [10]
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- Authors
- Darmanis, S., Sloan, S. A., Zhang, Y., Enge, M., Caneda, C., Shuer, L. M., Hayden Gephart, M. G., Barres, B. A., & Quake, S. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Neurobiology, and
- Neurosurgery, and
- Corresponding author
- Barres, Ben A.
- Quake, Stephen R.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-05-18
- Volume
- 112
- Issue
- 23
- Pages
- 7285-7290
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4466750
- OpenAlex
- W1552434751
- Cited by
- 1,401
- References
- 28
- Citations by year
- 2026: 68 · 2025: 101 · 2024: 163 · 2023: 143 · 2022: 150 · 2021: 161 · 2020: 166 · 2019: 144 · 2018: 119 · 2017: 94 · 2016: 73 · 2015: 17 · 2012: 1
- FWCI
- 43.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- California Institute for Regenerative Medicine (GC1R-06673)
- Svenska Sällskapet för Medicinsk Forskning
- National Institutes of Health
- National Heart, Lung, and Blood Institute (U01HL099995, U01HL099999)
- National Institute of Mental Health (F30MH106261, R01MH099555)
- National Institute of General Medical Sciences (T32GM007365)
- National Institute of Neurological Disorders and Stroke (R00NS089780, R01NS081703, K99NS089780)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- single-cell transcriptome, neuronal cell types, interneuron subtypes, glial cell types, temporal lobe, hippocampus, cell type classification
- MeSH terms
- Adult, Brain, HLA Antigens, Humans, Neurons, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome
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