Accessible high-throughput single-cell whole-genome sequencing with paired chromatin accessibility

Abstract

Summary: Single-cell whole-genome sequencing (scWGS) enables the assessment of genome-level molecular differences between individual cells with particular relevance to genetically diverse systems like solid tumors. The application of scWGS was limited due to a dearth of accessible platforms capable of producing high-throughput profiles. We present a technique that leverages nucleosome disruption methodologies with the widely adopted 10× Genomics ATAC-seq workflow to produce scWGS profiles for high-throughput copy-number analysis without new equipment or custom reagents. We further demonstrate the use of commercially available indexed transposase complexes from ScaleBio for sample multiplexing, reducing the per-sample preparation costs. Finally, we demonstrate that sequential indexed tagmentation with an intervening nucleosome disruption step allows for the generation of both ATAC and WGS data from the same cell, producing comparable data to the unimodal assays. By exclusively utilizing accessible commercial reagents, we anticipate that these scWGS and scWGS+ATAC methods can be broadly adopted by the research community. Motivation: Single-cell whole-genome sequencing (scWGS) is a powerful tool for studying complex, heterogeneous biology. The motivation for this study was to establish an scWGS method that relies only on commercially available reagents and instrumentation to make the technology accessible to the widest possible segment of the research community.

Keywords

• CP: Genetics
• CP: Biotechnology