Dey, S.S. et al. Nat. Biotechnol. 10.1038/nbt.3129 (19 January 2015).

Single-cell sequencing enables the study of tissue heterogeneity and rare cells, but it has been impossible to directly connect genotype with gene expression from such data. Dey et al. now describe genomic DNA–mRNA sequencing (DR-Seq), a method to obtain both types of information from the same cell. In DR-Seq, the contents of a single lysed cell are subjected to linear RNA amplification based on the CEL-Seq (cell expression by linear amplification and sequencing) protocol and quasilinear amplification of DNA based on the MALBAC (multiple annealing and looping-based amplification cycles) protocol. The DNA and RNA templates are not separated before amplification, thereby reducing the chances of contamination and material loss. The researchers applied DR-Seq to mouse embryonic stem cells and a breast cancer cell line, finding that high gene copy numbers may increase gene expression variability between cells.