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Nature, 10 April 2024 | https://doi.org/10.1038/s41586-024-07292-5 Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain

Changuk Chung ^1,2,11, Xiaoxu Yang ^1,2,3,11, Robert F. Hevner ^4,5, Katie Kennedy ⁶, Keng Ioi Vong ^1,2, Yang Liu ^1,2, Arzoo Patel^1,2, Rahul Nedunuri ^1,2, Scott T. Barton ⁷, Geoffroy Noel ⁸, Chelsea Barrows ^1,2, Valentina Stanley ^1,2, Swapnil Mittal ^1,2, Martin W. Breuss ⁹, Johannes C. M. Schlachetzki ^1,10, Stephen F. Kingsmore ² & Joseph G. Gleeson ^1,2 ,*

¹Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
²Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA.
³Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
⁴Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
⁵Department of Pathology, UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁶BioSkryb Genomics Inc., Durham, NC, USA.
⁷Division of Medical Education, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁸Division of Anatomy, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁹Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁰Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
¹¹These authors contributed equally: Changuk Chung, Xiaoxu Yang.

^*Corresponding author: correspondence to Joseph G. Gleeson

Abstract

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1⁺ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior–posterior axis precedes restriction in the dorsal–ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-11)
연구진국외 연구진
분야 의약학 > 유전 및 유전체의학

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