TY - JOUR
T1 - The origins and functional effects of postzygotic mutations throughout the human life span
AU - Rockweiler, Nicole B.
AU - Ramu, Avinash
AU - Nagirnaja, Liina
AU - Wong, Wing H.
AU - Noordam, Michiel J.
AU - Drubin, Casey W.
AU - Huang, Ni
AU - Miller, Brian
AU - Todres, Ellen Z.
AU - Vigh-Conrad, Katinka A.
AU - Zito, Antonino
AU - Small, Kerrin S.
AU - Ardlie, Kristin G.
AU - Cohen, Barak A.
AU - Conrad, Donald F.
N1 - Funding Information:
We thank the GTEx donors and families for their generous and selfless donation of tissues and organs for the advancement of science. We thank T. Lappalainen (New York Genome Center and KTH Royal Institute of Technology), H. Leitch (London Institute of Medical Sciences), G. Coop (UC Davis), I. Martincorena (Sanger Institute), the M. Griffiths laboratory (Washington University), the S. Montgomery laboratory (Stanford University), and the Conrad and Cohen laboratories (Washington University) for data sharing and helpful discussions. Sequencing for the validation experiments was performed by the Genome Technology Access Center (GTAC) in the Department of Genetics at Washington University School of Medicine. We appreciate obtaining access to de novo mutations on SFARI base (https://base.sfari.org). We thank the following funders for their support of the TwinsUK resource: Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), the National Institute for Health Research (NIHR)–funded BioResource Clinical Research Facility, and the Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. We also acknowledge that this manuscript includes several analyses that focus on GTEx donors with European and African American ancestry and less so on other ancestries in GTEx. This decision was made so that we would have higher statistical power to detect potentially rare genetic signals that may vary across populations. We hope that in future studies, larger numbers of Black, Indigenous, and People of Color are included so that we can learn about all populations in an equitable manner. Funding: This study was supported by National Institutes of Health grants R01MH101810 (to D.F.C.), R01HG007178 (to D.F.C.), and R01HD078641 (to D.F.C.); National Human Genome Research Institute grant T32HG000045 (to B.A.C.); and Medical Research Council grants MR/M004422/1 (to K.S.S.) and MR/R023131/1 (to K.S.S.). Author contributions: D.F.C. conceived the study. N.B.R. designed and performed research and analyzed data. W.H.W. and E.Z.T. assisted with experimental design and sample procurement and generated sequencing libraries for validation experiments. M.J.N. and L.N. performed and analyzed data from the sperm experiment. B.M. and A.Z. contributed to analyses. A.R., C.W.D., and N.H. contributed to the study design. K.A.V.-C. contributed to data visualization. D.F.C., K.G.A., and B.A.C. supervised the project. N.B.R. and D.F.C. wrote the manuscript in consultation with all authors. Competing interests: D.F.C. is an advisor to Paterna Biosciences. All other authors declare that they have no competing interests. Data and materials availability: All GTEx protected data are available through the database of Genotypes and Phenotypes (dbGaP) (accession no. phs000424.v8). Access to the raw sequence data is provided through the AnVIL platform (https://gtexportal.org/home/protectedDataAccess). The cancer results are based on data generated by the TCGA Research Network: https://www.cancer.gov/ccg/research/genome-sequencing/tcga. De novo mutations were obtained from denovo-db (https://denovo-db.gs.washington.edu/denovo-db/). Data generated on GTEx tissues by the ENCODE project are available from https://www.encodeproject.org. Source code used in this study is available from https://github.com/conradlab/RockweilerEtAl. Archived source code at the time of publication is available from Zenodo (56). License information: Copyright © 2023 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse
Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023/4/14
Y1 - 2023/4/14
N2 - Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.
AB - Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remain unclear. To study the origins and functional consequences of PZMs, we generated a multitissue atlas of PZMs spanning 54 tissue and cell types from 948 donors. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, and 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle. Thus, methods for interpreting effects across the body and the life span are needed to fully understand the consequences of genetic variants.
UR - http://www.scopus.com/inward/record.url?scp=85152444910&partnerID=8YFLogxK
U2 - 10.1126/science.abn7113
DO - 10.1126/science.abn7113
M3 - Article
C2 - 37053313
AN - SCOPUS:85152444910
SN - 0036-8075
VL - 380
JO - Science
JF - Science
IS - 6641
M1 - eabn7113
ER -