We develop methods to determine all classes of genetic variants in the genome of a single cell, as well as the RNA molecules the cell transcribes, to enable the exploration of the genetic differences between cells in a person's body and the relation of this diversity to disease.
The nature and pace of genome mutation in normal and diseased cells is largely unknown. Sequencing the DNA of single cells is a powerful method to study genome mutation in cells, right down to each generation of the cell. It will also enable the dissection and comparison of the genetic content of individual cells in normal organs and diseased tissues, providing insights into how fundamental processes of genome maintenance operate, how these processes may be perturbed in disease, and how somatic mutation may cause disease. Furthermore, single-cell genomics will accelerate our understanding of the genetic diversity that develops in a person's cells over time and its relation to phenotypes and disease development.
Conventional genome-sequencing and transcriptome-sequencing methods require respectively DNA and RNA extracted from a large population of cells. Hence, the genome and transcriptome compositions of individual cells are lost and de novo mutation in cell(s) can be concealed in the bulk signal. Analysis of single cells is essential when dissecting the genomic and transcriptomic makeup of tissues that comprise a population of heterogeneous cells to understand fundamental aspects of genome stability as well as the biology of cellular heterogeneity in health and disease.
Using single-cell DNA or RNA amplification methods sufficient material can be generated to allow sequencing. However, the interpretation of single-cell sequencing data is complicated by various amplification biases introduced in the cell's DNA or RNA sample and requires dedicated computational approaches to sift these amplification artefacts from true genetic changes.
We develop single-cell sequencing approaches to reliably detect genomic and transcriptomic variation across cells.
In particular we use these methods to study:
genome instability during gametogenesis and embryogenesis. Genome instability in the embryo not necessarily undermines normal human development, but may lead to a spectrum of conditions, including loss of conception, congenital genetic disorders and (mosaic) genetic variation development.
the nature and rate of DNA-mutation in different cell types to the per cell cycle level.
the extent, nature and biology of cellular heterogeneity in health and disease.
Key tools: We are pioneering single-cell multi-omics sequencing technologies, and have previously developed G&T-seq, a method for genome and transcriptome sequencing of the same single cell (Macaulay et al. Nature Methods. 2015 Jun;12(6):519-22). G&T-seq was further developed to DNA methylome and transcriptome sequencing of the same single cell (Angermueller et al. Nature Methods. 2016 Mar;13(3):229-232.).
The International Human Cell Atlas initiative aims to create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.
We have been granted a strategic award from the Wellcome Trust 'The Homunculus in our Thymus: A Cellular Genomics Approach' that enables us to investigate how thymic epithelial cells (TEC) - irrespective of their cell identity - remarkably can express virtually the complete set of protein-coding genes. These studies are relevant to better understand the fundamental function of the immune system and to identify causes of autoimmune diseases.
Programmes, Associate Research Programmes and Facilities
The Cancer, Ageing and Somatic Mutation Programme seeks to provide leadership in data aggregation and informatics innovation, developing high-throughput cellular models of cancer for genome-wide functional screens and drug testing, and exploring basic scientific questions about the role somatic mutation plays in clonal evolution, ageing and development.
Throughout life, the genome within cells of the human body is exposed to DNA damage and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. The Cancer Genome Project uses high-throughput genome sequencing to identify these somatically acquired mutations with the aim of characterising cancer genes, mutational processes and patterns of clonal evolution in human tumours.
We use cutting edge single cell genomics technologies and computational methods to understand genes, proteins and cells in human health and disease. We have a long-standing interest in understanding global principles of gene regulation, protein interactions and have a particular interest in immunity.