Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic si...

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Published inbioRxiv : the preprint server for biology
Main Authors Kim, Sonia Nan, Viswanadham, Vinayak V, Doan, Ryan N, Dou, Yanmei, Bizzotto, Sara, Khoshkhoo, Sattar, Huang, August Yue, Yeh, Rebecca, Chhouk, Brian, Truong, Alex, Chappell, Kathleen M, Beaudin, Marc, Barton, Alison, Akula, Shyam K, Rento, Lariza, Lodato, Michael, Ganz, Javier, Szeto, Ryan A, Li, Pengpeng, Tsai, Jessica W, Hill, Robert Sean, Park, Peter J, Walsh, Christopher A
Format Journal Article
LanguageEnglish
Published United States 06.11.2023
Subjects
single-cell transcriptomics
Somatic mutations
visual cortex
spatial genomics
excitatory neurons
lineage tracing
cortical development
inhibitory neurons
interneurons
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Summary:The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.