Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain

Lake, Blue B.; Ai, Rizi; Kaeser, Gwendolyn E.; Salathia, Neeraj; Yung, Yun C.; Li, Rui; Wildberg, André; Gao, Derek; Fung, Ho-Lim; Song, Chen; Vijayaraghavan, Raakhee; Wong, Julian; Chen, Allison; Sheng, Xiaoyan; Kaper, Fiona; Shen, Richard; Ronaghi, Mostafa; Fan, Jian‐Bing; Wang, Wei; Chun, Jerold; Zhang, Kun

doi:10.1126/science.aaf1204

Cited by 887 publications

(981 citation statements)

References 37 publications

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“…New cell types have been found in the brain [3][4][5][6][7] , gut 8 , retina 9 and immune system 10 , and these discoveries have yielded new insight -into how the immune system 11 functions, for example, and into the dynamics of tumour ecosystems 12 . Yet, to take the next step -to build a human cell atlas that is truly useful -requires taking the long view and addressing various systemic and organizational challenges, as well as technical and scientific ones.…”

Section: Technology Revolutionmentioning

confidence: 99%

The Human Cell Atlas: from vision to reality

Rozenblatt-Rosen

Stubbington

Regev

et al. 2017

Nature

566

399

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Section: Technology Revolutionmentioning

confidence: 99%

The Human Cell Atlas: from vision to reality

Rozenblatt-Rosen

Stubbington

Regev

et al. 2017

Nature

566

399

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“…However, other more complex organs such as the brain do not exhibit a corresponding number of 15 expressed genes despite the fact that they consist of a substantially greater number of distinct cell types 3,10, [14][15][16] . Moreover, recent animal studies have shown that many testis-enriched and evolutionarily-conserved genes are not required for male fertility in mice 17 .…”

Section: Main Textmentioning

confidence: 99%

Widespread transcriptional scanning in the testis modulates gene evolution rates

Xia

Yan

et al. 2018

Preprint

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Abstract:A long-standing question in molecular biology relates to why the testes express the largest number of genes relative to all other organs. Here, we report a detailed gene expression map of human spermatogenesis using single-cell RNA-Seq. Surprisingly, we found that 20 spermatogenesis-expressed genes contain significantly fewer germline mutations than unexpressed genes, with the lowest mutation rates on the transcribed DNA strands. These results suggest a model of 'transcriptional scanning' to reduce germline mutations by correcting DNA damage. This model also explains the rapid evolution in sensory-and immune-defense related genes, as well as in male reproduction genes. Collectively, our results indicate that widespread 25 expression in the testes achieves a dual mechanism for maintaining the DNA integrity of most genes, while selectively promoting variation of other genes.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/282129 doi: bioRxiv preprint first posted online Mar. 14, 2018; 2 Main Text:Human tissues and organs are distinguished by the genes that they express and those that they do not 1,2 . Tissues have transcriptomes of different complexities in terms of uniquely-expressed genes, as well as those genes expressed at differential levels [3][4][5][6] . One overarching goal in the life sciences is to characterize the specific transcriptomic signatures of all human tissues, and 5 ultimately each different cell type at the single-cell level 7 .In males, the testis is unique in comparison with somatic tissues in that it contains germ cells which pass the genetic information on to the next generation 8 . Interestingly, it has been known for many years that the testis stands out as having the most complex transcriptome with the highest number of expressed genes [9][10][11][12] . Widespread transcription in the testes has been 10 reported to account for an amazing expression of over 80% of all our protein-coding genes 10,11,13 , as well as across many other mammals 3,10 .Several hypotheses have been proposed to explain this observation. Widespread expression may represent a functional requirement for the gene-products in question 12 .However, other more complex organs such as the brain do not exhibit a corresponding number of 15 expressed genes despite the fact that they consist of a substantially greater number of distinct cell types 3,10,14-16 . Moreover, recent animal studies have shown that many testis-enriched and evolutionarily-conserved genes are not required for male fertility in mice 17 . A second hypothesis implicates leaky transcription during the massive chromatin remodeling that occurs throughout spermatogenesis 12,18,19 . However, this model predicts more expression during later stages of 20 spermatogenesis -when the genome is undergoing the most chromatin changes -contradicting ...

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“…The analyses conducted across as many as 170 brain regions and subregions (Hawrylycz et al 2012), 16 neuronal subtypes (Lake et al 2016), and 466 individual cells (Darmanis et al 2015) revealed the complex transcriptional landscape. Hence, integrated analyses of multiple brain regions in the context of human evolution may uncover alterations in spatial profiles of expression levels, revealing changes that collectively contribute to human brain functionality.…”

mentioning

confidence: 99%

Human-specific features of spatial gene expression and regulation in eight brain regions

Efimova

et al. 2018

Genome Res.

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Molecular maps of the human brain alone do not inform us of the features unique to humans. Yet, the identification of these features is important for understanding both the evolution and nature of human cognition. Here, we approached this question by analyzing gene expression and H3K27ac chromatin modification data collected in eight brain regions of humans, chimpanzees, gorillas, a gibbon, and macaques. An analysis of spatial transcriptome trajectories across eight brain regions in four primate species revealed 1851 genes showing human-specific transcriptome differences in one or multiple brain regions, in contrast to 240 chimpanzee-specific differences. More than half of these human-specific differences represented elevated expression of genes enriched in neuronal and astrocytic markers in the human hippocampus, whereas the rest were enriched in microglial markers and displayed human-specific expression in several frontal cortical regions and the cerebellum. An analysis of the predicted regulatory interactions driving these differences revealed the role of transcription factors in species-specific transcriptome changes, and epigenetic modifications were linked to spatial expression differences conserved across species.

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Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain

Cited by 887 publications

References 37 publications

The Human Cell Atlas: from vision to reality

The Human Cell Atlas: from vision to reality

Widespread transcriptional scanning in the testis modulates gene evolution rates

Human-specific features of spatial gene expression and regulation in eight brain regions

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