Universität zu Köln

Johnen, Ronja ORCID: 0000-0002-5150-5266 (2025). Single-cell mapping of somatic copy number alterations in healthy tissue using single-cell RNA sequencing data. PhD thesis, Universität zu Köln.

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Abstract

The elucidation and role of the occurrence of somatic copy number alterations (CNAs) in healthy human tissues is of great importance for understanding their role in aging, cancer, and related diseases. The occurrence of somatic single nucleotide variants (SNVs) and small insertions and deletions (INDELs) in various healthy tissues has been systematically studied. However, this is not the case for somatic CNAs, as they are largely private to individual cells in healthy tissues, their investigation remains challenging. We leverage single-cell RNA sequencing (scRNA-seq) data for the detection of rare CNAs as it additionally facilitates cell type-specific profiling, enabling exploration of their functional effects in different tissues and cell types. Here, we present RNA2CNA, the first method for identifying somatic CNAs in single cells from healthy tissue using scRNA-seq data. We validate RNA2CNA utilizing large reference datasets and demonstrate that it outperforms existing CNA calling methods in the identification of CNAs in healthy tissue. By applying RNA2CNA to large human datasets we provide the first comprehensive mutational map of CNAs in different human tissues and cell types. We unveil an age-related increase in somatic CNA events, suggesting that CNA events may significantly contribute to age-related phenotypes. Notably, our analysis reveals prevalent somatic CNAs in healthy tissues, including amplifications of pro-oncogenes and deletions of tumor suppressor genes. This suggests the existence of selective pressures in healthy cells and hints at the potential for early oncogenic event detection. Furthermore, we identify a protective state against cancer within a subset of endothelial cells in healthy tissue, hypothesizing that mutations in cancer driver genes may confer a "protective" effect on normal tissue. By examining the downstream effects of CNAs on functional processes in healthy human cells, we propose a hypothesis positing that somatic CNAs disrupt the stoichiometry of ribosomal components, resulting in increased translational stress. This stress may induce a subsequent reduction in translation as an adaptive response to conserve energy. RNA2CNA represents a significant advancement in characterizing somatic CNAs in healthy tissues and understanding their functional consequences. Our study offers insight into the role of somatic mutations in healthy human cells and sheds light on normal tissue development, maintenance, and potential neoplastic transformation.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Johnen, Ronja ronja.johnen@web.de orcid.org/0000-0002-5150-5266 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-753379
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Data processing Computer science Life sciences
Uncontrolled Keywords:	Keywords Language somatic mutations English single-cell RNA sequencing English copy number alterations English
Date of oral exam:	22 July 2024
Referee:	Name Academic Title Beyer, Andreas Prof. Dr. Tresch, Achim Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/75337