Relationship of Somatic Structural Variation Mosaicism to Aging and Disease Phenotypes

Project Information

MOSAIC

Grant agreement ID: 773026

DOI

10.3030/773026

Project closed

EC signature date 26 April 2018

Start date 1 February 2019

End date 31 March 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 997 060,00

EU contribution

€ 1 997 060,00

Coordinated by

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Germany

Periodic Reporting for period 4 - MOSAIC (Relationship of Somatic Structural Variation Mosaicism to Aging and Disease Phenotypes)

Reporting period: 2023-08-01 to 2024-03-31

Summary of the context and overall objectives of the project

Next-generation sequencing and single-cell-based technologies have shown that a person’s genome in the cells of our body over time.
External pressure and the need to grow and repair tissues places our individual cells at constant risk of acquiring mutations. As we age, tissues become a jigsaw of distinct sub-populations of cells carrying distinct hereditary information, a phenomenon known as somatic mosaicism. Specifically structural variants (SVs; e.g. deletions and inversions - large chunks of DNA differing between genomes of individual cells account for most varying bases in the human genome and are thought to be a key contributor to somatic mosaicisms.

The aim of this study was to uncover the extent and impact of SV mosaicism in two kinds of human tissue. In order to do so, we pursued single cell analyses using novel cutting-edge technologies, which offered the most direct way to detect somatic SVs and allowed us to functionally characterize these variations in individual cells.
Copy-neutral SV classes (e.g. inversions and translocations) are usually missed in conventional methods, including bulk DNA sequencing and single cell DNA sequencing approaches, which are limited to the identification of copy-number variants (CNVs).
We harnessed our newly developed experimental and computational tools based on the DNA template strand sequencing single cell technology (Strand-seq_ to construct a single cell catalog of a wide variety of relevant copy-neutral and copy-imbalanced SV classes in the blood compartment and the skin during human aging. Using this catalog, we aimed to study the functional impact of SV mosaicism on the cellular level, as a foundation for elucidating roles of somatic SVs in age-related phenotypes and diseases.
The understanding of the common role of SV mosaicism on aging and disease, had a significant impact in the field of human lifescience and research.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We were able to make major achievements and to publish 11important publications. We successfully developed references for normal human genetic variation including for inversions, which formed a crucial basis for conducting the MOSAIC project. We successfully developed an approach which enables the inference of multiple classes of SVs in single cells and were able to demonstrate the activity of particular SV mutational processes. As it is important for the scale of our experiments, we also successfully increased the throughput of our single cell studies and in addition, established a novel single-cell multi-omics method allowing us to functionally characterize somatic mosaicisms in humans - by directly linking genotype and phenotype in the same cell. Harnessing these ground-breaking tools, we made significant progress by identifying mosaic SVs with their cell-type specific contexts in the human blood compartment. We also initiated further work to functionally follow up these research findings (to be published in future papers).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our work by Ebert et al. published in Science in 2021 resulted in a paradigm change in terms of how human genomes can be analyzed - with wide implications for research and personalized medicine. For this, we were coupling different DNA sequencing platforms (Strand-seq and long read sequencing) allowing us to sequence assemble and characterize variation in 64 diverse haplotype-resolved genomes.

Our work by Sanders et al. published in Nature Biotechnology in 2020 describes the first method that discovers the full spectrum of somatic SVs - the most common driver mutation class in cancer - in single cells, at a resolution of 200 kilobasepairs, and as such has wide implications for research on somatic mosaicism and cancer.

Our work by Porubsky et al. published in Cell in 2022 highlighted how copy-neutral structural variations (i.e. inversions) can contribute to increased mutability and predisposition to disease-causing copy number vari-ation in sex chromosomes.

Our work published in Jeong et. al (Nature Biotechnology 2023) allowed for the first time to link structural mutations comprehensively with their phenotypic outcomes - a major advance in the single cell genomics field.

Our work by Grimes et al. (published in Nature Genetics in 2024) underscored the contribution of mosaic structural variants to the cellular and molecular phenotypes associated with the aging hematopoietic sys-tem, and established a foundation for deciphering the molecular links between mosaic SVs, aging and dis-ease susceptibility in normal tissues.

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