GENESIS: Generating scRNA-Seq data from Multiome Gene Expression

Single-cell technologies have significantly advanced our understanding of cellular heterogeneity by allowing the examination of individual cells at high resolution. Traditional single-cell RNA sequencing (scRNA-Seq) methods, which utilise whole cells, capture comprehensive RNA content. In contrast, emerging Multiome technologies, which simultaneously profile multiple omics such as gene expression (GEX) and chromatin accessibility, rely on nuclear RNA, potentially missing key cytoplasmic information. This discrepancy leads to substantial technical and biological differences between GEX and scRNA-Seq datasets, making it difficult to integrate data and perform downstream tasks like cell-type classification. To address this challenge, we introduce GENESIS (Gene Expression Normalisation and Enhancement for Single-cell Integrated Sequencing), a novel computational framework designed to transform GEX data from Multiome experiments into enhanced, scRNA-Seq like profiles. Utilising advanced generative models—including Variational Autoencoders, Generative Adversarial Networks, and a tailored VAE UNet architecture—GENESIS can generate high-quality data by modelling and compensating for the inherent differences between nuclear and cytoplasmic RNA. Our comprehensive evaluations show that GENESIS, particularly through the VAE UNet model, generates synthetic scRNA-Seq data that closely resembles the resolution and biological accuracy of whole-cell sequencing, improving downstream tasks, especially cell-type classification.