TY - JOUR
T1 - Landmarks of human embryonic development inscribed in somatic mutations
AU - NIMH Brain Somatic Mosaicism Network
AU - Bizzotto, Sara
AU - Dou, Yanmei
AU - Ganz, Javier
AU - Doan, Ryan N.
AU - Kwon, Minseok
AU - Bohrson, Craig L.
AU - Kim, Sonia N.
AU - Bae, Taejeong
AU - Abyzov, Alexej
AU - Park, Peter J.
AU - Walsh, Christopher A.
N1 - Funding Information:
This work was supported by National Institute of Mental Health (NIMH Brain Somatic Mosaicism Network grant U01MH106883 to C.A.W. and P.J.P.); NINDS (grant R01NS032457 to C.A.W. and P.J.P.); and the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation. Boston Children's Hospital Intellectual and Developmental Disabilities Research Center is funded by NIH grant U54HD090255. S.B. was supported by the Manton Center for Orphan Disease Research at Boston Children's Hospital. J.G. was supported by a Basic Research Fellowship from the American Brain Tumor Association (BRF1900016) and by Brain SPORE grant P50CA165952. S.N.K. is a Stuart H.Q. & Victoria Quan fellow at Harvard Medical School. C.A.W. is an investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/3/19
Y1 - 2021/3/19
N2 - 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.
AB - 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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U2 - 10.1126/science.abe1544
DO - 10.1126/science.abe1544
M3 - Article
C2 - 33737485
AN - SCOPUS:85103061603
SN - 0036-8075
VL - 371
SP - 1249
EP - 1253
JO - Science
JF - Science
IS - 6535
ER -