@article{de8d6c08082a4fad97debc95688a233d,
title = "Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements",
abstract = "Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.",
author = "Luquette, {Lovelace J.} and Miller, {Michael B.} and Zinan Zhou and Bohrson, {Craig L.} and Yifan Zhao and Hu Jin and Doga Gulhan and Javier Ganz and Sara Bizzotto and Samantha Kirkham and Tino Hochepied and Claude Libert and Alon Galor and Junho Kim and Lodato, {Michael A.} and Garaycoechea, {Juan I.} and Charles Gawad and Jay West and Walsh, {Christopher A.} and Park, {Peter J.}",
note = "Funding Information: We thank R. S. Hill, R. Mathieu and L. (Sahithi) Cheemalamarri at the Boston Children{\textquoteright}s Hospital & Harvard Stem Cell Institute Flow Cytometry Research Facility, the Research Computing group at Harvard Medical School, and the Boston Children{\textquoteright}s Hospital Intellectual and Developmental Disabilities Research Center Molecular Genetics Core for assistance. Human tissue was obtained from the NIH Neurobiobank at the University of Maryland, and we thank the donors and families for their invaluable contributions to the advancement of science. This work was supported by the Bioinformatics and Integrative Genomics training grant (no. T32HG002295 to L.J.L.), grant nos. K08 AG065502 and T32 HL007627 (to M.B.M.), the Brigham and Women{\textquoteright}s Hospital Program for Interdisciplinary Neuroscience through a gift from Lawrence and Tiina Rand (to M.B.M.), the donors of the Alzheimer{\textquoteright}s Disease Research program of the BrightFocus Foundation (no. A20201292F to M.B.M.), the Doris Duke Charitable Foundation Clinical Scientist Development Award (no. 2021183 to M.B.M.), PRMRP Discovery Award (no. W81XWH2010028 to Z.Z.), the Edward R. and Anne G. Lefler Center postdoctoral fellowship (to Z.Z.), and grant nos. R00 AG054748 (to M.A.L.), R01 AG070921 (to C.A.W.) and R01NS032457 and U01MH106883 (to P.J.P. and C.A.W.), and the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation (to C.A.W.). C.A.W. is an investigator at the Howard Hughes Medical Institute. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: We thank R. S. Hill, R. Mathieu and L. (Sahithi) Cheemalamarri at the Boston Children{\textquoteright}s Hospital & Harvard Stem Cell Institute Flow Cytometry Research Facility, the Research Computing group at Harvard Medical School, and the Boston Children{\textquoteright}s Hospital Intellectual and Developmental Disabilities Research Center Molecular Genetics Core for assistance. Human tissue was obtained from the NIH Neurobiobank at the University of Maryland, and we thank the donors and families for their invaluable contributions to the advancement of science. This work was supported by the Bioinformatics and Integrative Genomics training grant (no. T32HG002295 to L.J.L.), grant nos. K08 AG065502 and T32 HL007627 (to M.B.M.), the Brigham and Women{\textquoteright}s Hospital Program for Interdisciplinary Neuroscience through a gift from Lawrence and Tiina Rand (to M.B.M.), the donors of the Alzheimer{\textquoteright}s Disease Research program of the BrightFocus Foundation (no. A20201292F to M.B.M.), the Doris Duke Charitable Foundation Clinical Scientist Development Award (no. 2021183 to M.B.M.), PRMRP Discovery Award (no. W81XWH2010028 to Z.Z.), the Edward R. and Anne G. Lefler Center postdoctoral fellowship (to Z.Z.), and grant nos. R00 AG054748 (to M.A.L.), R01 AG070921 (to C.A.W.) and R01NS032457 and U01MH106883 (to P.J.P. and C.A.W.), and the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation (to C.A.W.). C.A.W. is an investigator at the Howard Hughes Medical Institute. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = oct,
doi = "10.1038/s41588-022-01180-2",
language = "English",
volume = "54",
pages = "1564--1571",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",
}