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Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells

View ORCID ProfileCaleb A. Lareau, Sonia M. Dubois, Frank A. Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D. Praktiknjo, Patrick Maschmeyer, Jeffrey M. Verboon, Jacob C. Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D. Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Ansuman T. Satpathy, Aviv Regev, Vijay G. Sankaran, Suneet Agarwal, View ORCID ProfileLeif S. Ludwig
doi: https://doi.org/10.1101/2022.11.20.517242
Caleb A. Lareau
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
2Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA
3Department of Genetics, Stanford University, Stanford, CA 94305, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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  • ORCID record for Caleb A. Lareau
  • For correspondence: clareau@stanford.edu aviv.regev.sc@gmail.com sankaran@broadinstitute.org suneet.agarwal@childrens.harvard.edu leif.ludwig@bih-charite.de
Sonia M. Dubois
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Frank A. Buquicchio
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Yu-Hsin Hsieh
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
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Kopal Garg
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Pauline Kautz
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
8Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany
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Lena Nitsch
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
9Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany
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Samantha D. Praktiknjo
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
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Patrick Maschmeyer
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
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Jeffrey M. Verboon
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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Jacob C. Gutierrez
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Yajie Yin
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Evgenij Fiskin
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Wendy Luo
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Eleni Mimitou
10Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
16Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Christoph Muus
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
11Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02134, USA
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Rhea Malhotra
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Sumit Parikh
12Center for Pediatric Neurosciences, Mitochondrial Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
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Mark D. Fleming
13Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Lena Oevermann
14Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany
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Johannes Schulte
14Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany
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Cornelia Eckert
14Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany
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Anshul Kundaje
3Department of Genetics, Stanford University, Stanford, CA 94305, USA
15Department of Computer Science, Stanford University, Stanford, CA 94305, USA
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Peter Smibert
10Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA
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Ansuman T. Satpathy
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
2Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA
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Aviv Regev
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
16Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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  • For correspondence: clareau@stanford.edu aviv.regev.sc@gmail.com sankaran@broadinstitute.org suneet.agarwal@childrens.harvard.edu leif.ludwig@bih-charite.de
Vijay G. Sankaran
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: clareau@stanford.edu aviv.regev.sc@gmail.com sankaran@broadinstitute.org suneet.agarwal@childrens.harvard.edu leif.ludwig@bih-charite.de
Suneet Agarwal
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: clareau@stanford.edu aviv.regev.sc@gmail.com sankaran@broadinstitute.org suneet.agarwal@childrens.harvard.edu leif.ludwig@bih-charite.de
Leif S. Ludwig
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
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  • ORCID record for Leif S. Ludwig
  • For correspondence: clareau@stanford.edu aviv.regev.sc@gmail.com sankaran@broadinstitute.org suneet.agarwal@childrens.harvard.edu leif.ludwig@bih-charite.de
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Abstract

Cells experience intrinsic and extrinsic pressures that affect their proclivity to expand and persist in vivo. In congenital disorders caused by loss-of-function mutations in mitochondrial DNA (mtDNA), metabolic vulnerabilities may result in cell-type specific phenotypes and depletion of pathogenic alleles, contributing to purifying selection. However, the impact of pathogenic mtDNA mutations on the cellular hematopoietic landscape is not well understood. Here, we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from Pearson syndrome patients. We resolve the interdependence between pathogenic mtDNA and lineage, including purifying selection against deletions in effector/memory CD8 T-cell populations and recent thymic emigrants and dynamics in other hematopoietic populations. Our mapping of lineage-specific purifying selection dynamics in primary cells from patients carrying pathogenic heteroplasmy provides a new perspective on recurrent clinical phenotypes in mitochondrial disorders, including cancer and infection, with potential broader relevance to age-related immune dysfunction.

Competing Interest Statement

The Broad Institute has filed for a patent relating to the use of the technology described in this paper where CAL, LSL, CM, AR, and VGS are named inventors (US provisional patent application 62/683,502). CAL and LSL are consultants to Cartography Biosciences. ATS is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. AR is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, AR is an employee of Genentech and has equity in Roche. VGS serves as an advisor to and/or has equity in Branch Biosciences, Novartis, Forma, Cellarity, and Ensoma.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173936

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells
Caleb A. Lareau, Sonia M. Dubois, Frank A. Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D. Praktiknjo, Patrick Maschmeyer, Jeffrey M. Verboon, Jacob C. Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D. Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Ansuman T. Satpathy, Aviv Regev, Vijay G. Sankaran, Suneet Agarwal, Leif S. Ludwig
bioRxiv 2022.11.20.517242; doi: https://doi.org/10.1101/2022.11.20.517242
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Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells
Caleb A. Lareau, Sonia M. Dubois, Frank A. Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D. Praktiknjo, Patrick Maschmeyer, Jeffrey M. Verboon, Jacob C. Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D. Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Ansuman T. Satpathy, Aviv Regev, Vijay G. Sankaran, Suneet Agarwal, Leif S. Ludwig
bioRxiv 2022.11.20.517242; doi: https://doi.org/10.1101/2022.11.20.517242

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