TY - JOUR
T1 - Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis
AU - Bae, Taejeong
AU - Tomasini, Livia
AU - Mariani, Jessica
AU - Zhou, Bo
AU - Roychowdhury, Tanmoy
AU - Franjic, Daniel
AU - Pletikos, Mihovil
AU - Pattni, Reenal
AU - Chen, Bo Juen
AU - Venturini, Elisa
AU - Riley-Gillis, Bridget
AU - Sestan, Nenad
AU - Urban, Alexander E.
AU - Abyzov, Alexej
AU - Vaccarino, Flora M.
N1 - Funding Information:
This work was supported by the high-performance computing (HPC) facilities operated by the Yale Center for Research Computing and Yale’s W. M. Keck Biotechnology Laboratory, as well as their respective staff. This work is also supported by NIH grants RR19895 and RR029676-01, which helped fund the cluster. The sequencing data from this study have been deposited to the NIH National Institute of Mental Health (NIMH) Data Archive (https://data-archive.nimh.nih.gov) under collection ID #2330 and DOI: 10.15154/1410419. This work was funded by the Mayo Clinic Center For Individualized Medicine and by NIH grants R01 MH100914 (F.M.V.), U01 MH106876 (F.M.V., A.A., A.E.U.), U01 MH106874 (N.S.), P50 MH106934 (N.S.), and R03 CA191421 (A.A.). A.A. is also a Visiting Professor at Yale Child Study Center. The supplementary materials contain additional data.
Publisher Copyright:
© The Authors 2017, some rights reserved
PY - 2018/2/2
Y1 - 2018/2/2
N2 - Somatic mosaicism in the human brain may alter function of individual neurons. We analyzed genomes of single cells from the forebrains of three human fetuses (15 to 21 weeks postconception) using clonal cell populations. We detected 200 to 400 single-nucleotide variations (SNVs) per cell. SNV patterns resembled those found in cancer cell genomes, indicating a role of background mutagenesis in cancer. SNVs with a frequency of >2% in brain were also present in the spleen, revealing a pregastrulation origin. We reconstructed cell lineages for the first five postzygotic cleavages and calculated a mutation rate of ~1.3 mutations per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted toward oxidative damage, and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit substantially more mutagenesis than adulthood.
AB - Somatic mosaicism in the human brain may alter function of individual neurons. We analyzed genomes of single cells from the forebrains of three human fetuses (15 to 21 weeks postconception) using clonal cell populations. We detected 200 to 400 single-nucleotide variations (SNVs) per cell. SNV patterns resembled those found in cancer cell genomes, indicating a role of background mutagenesis in cancer. SNVs with a frequency of >2% in brain were also present in the spleen, revealing a pregastrulation origin. We reconstructed cell lineages for the first five postzygotic cleavages and calculated a mutation rate of ~1.3 mutations per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted toward oxidative damage, and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit substantially more mutagenesis than adulthood.
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U2 - 10.1126/science.aan8690
DO - 10.1126/science.aan8690
M3 - Article
C2 - 29217587
AN - SCOPUS:85037705979
SN - 0036-8075
VL - 359
SP - 550
EP - 555
JO - Science
JF - Science
IS - 6375
ER -