한빛사 논문
Sara Bizzotto1,2,3,*, Yanmei Dou4,*, Javier Ganz1,2,3,*, Ryan N. Doan1, Minseok Kwon4, Craig L. Bohrson4, Sonia N. Kim1,2,3,5, Taejeong Bae6, Alexej Abyzov6, NIMH Brain Somatic Mosaicism Network†, Peter J. Park4,7,‡, Christopher A. Walsh1,2,3,‡
1Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA 02115, USA.
2Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
5PhD Program in Biological and Biomedical Sciences, Harvard University, Boston, MA 02115, USA.
6Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
7Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA.
‡Corresponding author.
*These authors contributed equally to this work.
†NIMH Brain Somatic Mosaicism Network members and affiliations are listed in the supplementary materials.
Abstract
Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as “endogenous barcodes” in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.
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