The aim of the Sanger Institute-EBI Single-Cell Genomics Centre is to develop and apply methods for capturing the complete genetic content of single cells in a high-throughput manner, allowing us to explore the nature and role of cellular heterogeneity in normal development and disease. The Centre is strengthened by the Single Cell Genomics Core Facility that implements state-of-the-art single-cell technologies and provides high throughput single-cell isolation and sequence library preparation services. Apart from wet-lab approaches, we also develop the computational means for the analysis of single cells.
Single-cell genome sequencing
Our knowledge on the nature and rate of genome mutation in a developing organism is rudimentary. In addition, the contributions of these mosaic somatic variants to phenotype and disease aetiology remain largely unknown. Standard methods sequence DNA that has been extracted from a population of cells, such that not only the genetic composition of individual cells is lost, but also de novo mutations in cell(s) are effectively concealed by the bulk signal. Single-cell genome analyses overcome these issues.
We are developing single-cell genome sequencing technologies to enable the discovery of the entire spectrum of DNA mutation –including the acquisition of ploidy changes, aneuploidies, copy number variants, structural variants, retrotranspositions, indels, and single nucleotide variants. The technology will answer burning questions on mutational burden in normal development and how this is impacted by germline genetic background, lifestyle, aging and disease.
Single-cell epigenome sequencing
Epigenomic mechanisms enable functional diversification of cells with identical genomes, and their study is fundamental to understanding cellular identity and function. However, the majority of our current understanding derives from interpreting average epigenomic signatures across large cell populations, masking epigenomic variation within the population of cells. We are developing single-cell epigenomics technologies to overcome these limitations, enabling the discovery and classification of novel subpopulations of cells, the unknown epigenomic repertoire of rare cells and to obtain deeper insight in epigenomic maintenance and reprogramming.
Single-cell transcriptome sequencing
We are developing wet-lab and computational methods to explore the transcriptomes of single cells, allowing for instance the discovery of novel cell types in complex tissues, the exploration of cell types/cell states and molecular processes involved in normal development and disease processes, and constructing roadmaps of cellular differentiation by pseudo-time ordering of single-cell transcriptomes.
1. Wellcome Trust Strategic Award project “Tracing early mammalian lineage decisions by single cell genomics”
Lewis Wolpert famously called gastrulation the most important time in your life. During this fascinating process, a pluripotent stem cell population in the early embryo gives rise to the three germ layers from which all organ systems develop. Cell signalling and transcriptional networks are known to regulate aspects of gastrulation, but the precise mechanisms have not been investigated at the single cell level. For our understanding of gastrulation to be taken to another level, we need to measure the molecular behaviour of each individual cell so that we can see how decisions about cell specialisation are taken. We are applying single cell sequencing techniques to profile the majority of the cells in mouse postimplantation embryos.
Partners – Wolf Reik, Sarah Teichmann, Berthold Gottgens, Harold Swerdlow, Thierry Voet, John Marioni, Shankar Srinivas, Jennifer Nichols, Benjamin David Simons
2. Wellcome Trust Strategic Award project “The Homunculus in our Thymus: A Cellular Genomics Approach”.
Thymic epithelial cells (TEC) avert autoimmunity through their ability to promiscuously express virtually the entire protein-coding gene repertoire as a molecular library against which immature T cells are selected. An integrative analysis of the transcriptome, epigenome and proteome of distinct TEC subpopulations will be used to attain an unparalleled systems-level understanding of the molecular conditions that select a tolerant T cell repertoire under normal physiological conditions. - Read more
Partners – Georg Hollander, Chris Ponting, John Marioni, Chris Schofield, Jon Chapman, Thierry Voet, Stephen Sansom
3. Wellcome Trust Technology development project “New genetic, imaging and microfluidics technologies for single cell genomics”
We are miniaturising single cell technologies to nano- and pico-litre droplet compartments paving the way to cheap high throughput processing of single cells.
Partners – Shankar Srinivas, Florian Hollfelder, Georg Hollander, John Marioni, Chris Ponting, Wolf Reik, Sarah Teichmann, Thierry Voet