Periodic Reporting for period 3 - MOSAIC (Relationship of Somatic Structural Variation Mosaicism to Aging and Disease Phenotypes)
Période du rapport: 2022-02-01 au 2023-07-31
With the advent of next-generation sequencing and, in particular, single-cell-based technologies, the long-held belief that a person's genome is stable over time has been challenged. Instead, external pressures and the need to grow and repair tissues places our cells at constant risk of acquiring mutations over time. As we age, tissues become a jigsaw of distinct sub-populations of cells carrying distinct hereditary information - this phenomenon is typically referred to as somatic mosaicism. Specifically structural variants (SVs; e.g. deletions and inversions - large chunks of DNA differing between genomes) account for most varying bases in the genome of our cells. The overarching aim of this study is to uncover the extent and impact of SV mosaicism in two human tissues. We are, in this regard, pursuing single cell analyses using novel cutting edge technologies, which offer the most direct way to detect somatic SVs and to functionally characterise them in individual cells. Performing SV analysis in single cells at scale, however, is not a mainstream approach: current methods identify copy-number variants (CNVs), but miss key copy-neutral SV classes (e.g. inversions and translocations). We are using our newly developed experimental and computational tools to construct a single cell catalog of a wide variety of relevant SV classes in the blood compartment and the skin during human aging. Using this catalog, we aim 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. An understanding of the common roles of SV mosaicism on aging and disease is expected to be of significant impact for human health research.
We were already able to make major achievements and to publish 6 important publications. 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, began implementing a novel single multi-omics method allowing us to functionally characterize somatic mosaicisms in humans - by directly linking genotype and phenotype in the same cell. We already made significant progress and identified mosaic SVs in several human bone marrow samples and started work to functionally follow up these results.
Our work by Ebert et al. published in Science in 2021 resulted in a paradigm change in terms of how human genomes can be analysed - with wide implications for research and personalised 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, and as such has wide implications for research on somatic mosaicism and cancer.
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, and as such has wide implications for research on somatic mosaicism and cancer.