Single-cell genomics - Associate Faculty group

Thierry Voet's Associate Faculty group focuses on developing methods that characterise the DNA and RNA in a single cell to enable the exploration of DNA-mutation, the genetic differences between cells in a person's body and the relation of this diversity to disease.

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 (per cell cycle). It will also enable the dissection and comparison of the genetic content of individual cells in normal organs and in cancers, providing insights into how fundamental processes of genome maintenance operate. Furthermore, single-cell genomics will accelerate our understanding of the genetic diversity that develops in a person's cells over time and the development of certain physical characteristics or disease.

We anticipate our methods will enable new clinical applications in genetic diagnosis.

[Thierry Voet]

Background

Conventional genome-sequencing and transcriptome-sequencing methods require DNA/RNA extracted from a population of cells. Hence, the genome and transcriptome compositions of individual cells are lost and de novo mutation in cell(s) is often concealed in the bulk signal. Analysis of single cells is essential when dissecting the genetic makeup of heterogeneous tissues to understand the causes of disease and phenotypes, and to perform basic genome stability research.

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 approaches to sift these amplification artefacts from true genetic changes.

Research

We develop single-cell sequencing approaches to reliably detect genetic changes in a cell. In particular we use these methods to study:

  1. genomic instability instigated during gametogenesis and embryogenesis. Embryonic genomic instability not necessarily undermines normal human development, but may lead to a spectrum of conditions, including loss of conception, congenital genetic disorders and genetic variation development
  2. the nature and rate of DNA-mutation to the per cell cycle level
  3. somatic genetic heterogeneity in healthy and diseased primary tissues. We are applying the methods to chart intratumor genetic heterogeneity.

Collaborations

We will be working closely with a number of Sanger Institute researchers, faculty and associate faculty members:

  • Cancer Genome Project - Wellcome Trust Sanger Institute, UK
  • Computational genomics - Wellcome Trust Sanger Institute, UK
  • SymBioSys, KU Leuven, Belgium

Selected Publications

  • Microarray analysis of copy number variation in single cells.

    Konings P, Vanneste E, Jackmaert S, Ampe M, Verbeke G, Moreau Y, Vermeesch JR and Voet T

    Nature protocols 2012;7;2;281-310

  • Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos.

    Voet T, Vanneste E, Van der Aa N, Melotte C, Jackmaert S, Vandendael T, Declercq M, Debrock S, Fryns JP, Moreau Y, D'Hooghe T and Vermeesch JR

    Human mutation 2011;32;7;783-93

  • The human cleavage stage embryo is a cradle of chromosomal rearrangements.

    Voet T, Vanneste E and Vermeesch JR

    Cytogenetic and genome research 2011;133;2-4;160-8

  • Chromosome instability is common in human cleavage-stage embryos.

    Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F, Fryns JP, Verbeke G, D'Hooghe T, Moreau Y and Vermeesch JR

    Nature medicine 2009;15;5;577-83

* quick link - http://q.sanger.ac.uk/4fo4w7xg