Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells
Schulte Johannes Lareau Caleb A Buquicchio Frank A. Garg Kopal Praktiknjo Samantha D. Maschmeyer Patrick Yin Yajie Oevermann Lena Kundaje Anshul Satpathy Ansuman T. Sankaran Vijay G. Ludwig Leif S. Fleming Mark D. Fiskin Evgenij Regev Aviv Muus Christoph Dubois Sonia M Smibert Peter Kautz Pauline Hsieh Yu-Hsin Malhotra Rhea Parikh Sumit Gutierrez Jacob C. Eckert Cornelia Agarwal Suneet Mimitou Eleni Verboon Jeffrey M. Luo Wendy Nitsch Lena
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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.引用本文复制引用
Schulte Johannes,Lareau Caleb A,Buquicchio Frank A.,Garg Kopal,Praktiknjo Samantha D.,Maschmeyer Patrick,Yin Yajie,Oevermann Lena,Kundaje Anshul,Satpathy Ansuman T.,Sankaran Vijay G.,Ludwig Leif S.,Fleming Mark D.,Fiskin Evgenij,Regev Aviv,Muus Christoph,Dubois Sonia M,Smibert Peter,Kautz Pauline,Hsieh Yu-Hsin,Malhotra Rhea,Parikh Sumit,Gutierrez Jacob C.,Eckert Cornelia,Agarwal Suneet,Mimitou Eleni,Verboon Jeffrey M.,Luo Wendy,Nitsch Lena.Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells[EB/OL].(2025-03-28)[2026-04-04].https://www.biorxiv.org/content/10.1101/2022.11.20.517242.学科分类
医学研究方法/基础医学/细胞生物学
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