DR-Seq: a new single-cell genomics method

Scientists at the Hubrecht Institute have developed the first integrated single-cell method for quantifying genomic DNA and mRNA from the same cell: DR-Seq. This method, which is described in a Nature Biotechnology article published this week, holds great promise for studying cell-to-cell heterogeneity in cancer biology. 

One of the central questions in biology is to understand how genetic variations influence the functioning of cells. Each individual cell in our body contains our genetic information, in the form of genomic DNA. How this genetic information is expressed, is determined by our mRNA, the molecule that is used to synthesize proteins that define the fate and function of individual cells. In the end these proteins determine whether a cell becomes a neuron, muscle cell, hair cell or any other cell.

DR-Seq method 
Over the last decade, understanding how genetic variations influence the behaviour of cells on a genome-wide scale has been investigated using a technique called next-generation sequencing. Next-generation sequencing based methods traditionally require starting with a large population of cells. When studying the behaviour of complex tissues that are often composed of several cell types or tumour populations that are very heterogeneous, such methods only provide an average description of the biological system.

Advances in molecular biology over the last few years has led to the development of methods that allow sequencing the genome or mRNA from single cells. Such single-cell sequencing methods allow researchers to explore the variability that exists between individual cells. However, as these single-cell technologies are limited to quantifying either the genome or mRNA, it is currently impossible to explore which genetic variations directly influence gene expression in single cells. With the development of DR-Seq, it is possible to quantify both the genome and mRNA from a same single cell simultaneously.

Application
Genome-wide analysis of single cells using DR-Seq enables better understanding of how genetic variations influence the behaviour of individual cells and therefore holds great promise for cancer biology. Recent evidence suggests that heterogeneity within a tumour could lead to cancer subpopulations. These subpopulations potentially have different properties that could create small subsets being immune to drug therapy. DR-Seq would be ideally suited to identify and characterize genetic variations within these cancer subpopulations. This allows not only better understanding of the origin and evolution of tumours, but also helps with possibly developing better treatments in future. Furthermore, DR-Seq could be a helpful tool for studying other cells in our body like neurons. For example, a small number of neurons, in healthy and diseased states, show genetic variations between individual cells. Using DR-Seq, the functional consequences of these genomic variations can be investigated, which could give insights into several brain diseases.