Integrated genome and transcriptome sequencing from the same cell

Single-cell genomics and single-cell transcriptomics have recently emerged as powerful tools to study the biology of single cells at a genome-wide scale. However, a major challenge is to quantify both genomic DNA and mRNA from the same cell, which would allow direct comparison of genomic variation and transcriptome heterogeneity. Here we describe a method that allows the sequencing of genomic DNA and mRNA from the same cell without physical separation of the nucleic acids prior to amplification. We show that such an integrated strategy achieves efficiency similar to methods that sequence either genomic DNA or mRNA from single cells. We use this method to correlate DNA copy number variation to transcriptome variability among individual cells. Finally, we show that genes that display more cell-to-cell variability in transcript numbers are generally associated with reduced copy number loci and vice-versa, implying that copy number variations could potentially drive variability in gene expression between single cells.