JOINTLY: interpretable joint clustering of single-cell transcriptomes

Abstract Single-cell and single-nucleus RNA-sequencing (sxRNA-seq) is increasingly being used to characterise the transcriptomic state of cell types at homeostasis, during development and in disease. However, this is a challenging task, as biological effects can be masked by technical variation. Here, we present JOINTLY, an algorithm enabling joint clustering of sxRNA-seq datasets across batches. JOINTLY performs on par or better than state-of-the-art batch integration methods in clustering tasks and outperforms other intrinsically interpretable methods. We demonstrate that JOINTLY is robust against over-correction while retaining subtle cell state differences between biological conditions and highlight how the interpretation of JOINTLY can be used to annotate cell types and identify active signalling programs across cell types and pseudo-time. Finally, we use JOINTLY to construct a reference atlas of white adipose tissue (WATLAS), an expandable and comprehensive community resource, in which we describe four adipocyte subpopulations and map compositional changes in obesity and between depots