When we talk about sequencing, it’s easy to forget just how much complexity hides inside a “bulk” sample. Mix thousands or millions of cells together, and the signal from rare but important variants soon gets averaged away. Yet it’s often those rare events, for example, the single resistant cancer cell, or the neuron carrying a mosaic mutation, that end up shaping disease outcomes.
That’s why single-cell analysis has become such a powerful tool. Most assays, however, still force you to choose between DNA or RNA, giving only half the picture. Genomics reveals the variants, mutations, or structural changes that set the stage for disease. Transcriptomics captures the gene expression programs, isoforms, and fusion events that drive cellular behavior. But to truly understand the underlying biology, you need both. At the same resolution. From the same cell.
This is where single-cell multiomic technologies like BioSkryb’s ResolveOME™ and ResolveSEQ LongRead are changing the game. These platforms unify single-cell genome and transcriptome sequencing to give researchers a valuable window into how genotype and phenotype connect at the single-cell level.
Eremid® is the only long-read GLP and CAP-accredited/CLIA-certified Certified Service Provider (CSP) for BioSkryb offering these platforms. In this blog, we’ll delve into the technology itself and explore how it’s already making a difference across diverse fields from oncology and neuroscience to cell and gene therapy, rare diseases and agriculture.
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How ResolveOME powers single-cell multiomics
At its core, ResolveOME is designed to solve one of the biggest frustrations in single-cell biology: the need to split precious material between different assays. Instead of forcing researchers to choose between DNA and RNA, ResolveOME captures both, in full, from the same cell.
The key to this is BioSkryb’s patented Primary Template–directed Amplification (PTA) chemistry. Unlike traditional whole-genome amplification methods, PTA avoids the uneven coverage and allelic dropout that can obscure rare but important variants. The result is remarkably complete data: up to ~97% genomic coverage with high allelic balance.
Figure 1: ResolveOME end-to-end workflow
On the RNA side, ResolveOME gives a comprehensive picture of the transcriptome by capturing full-length mRNA. This delivers valuable isoform resolution and fusion detection that droplet-based single-cell RNA-seq often misses. Put together, you can track single-nucleotide variants (SNVs), copy-number variation (CNV), and structural changes in the genome, while simultaneously mapping how those changes alter gene expression and transcript structure.
In other words, ResolveOME connects genotype to phenotype at single-cell resolution: the foundation for understanding how genetic variation drives cellular behavior.
Unlocking the benefits of long reads with ResolveSEQ LongRead
While short-read sequencing has powered most of the single-cell revolution, the technique inevitably leaves some blind spots. Complex genomic regions, tandem repeats, structural rearrangements and large edits can be hard to resolve by reading short fragments alone. That’s where BioSkryb’s ResolveSEQ LongRead kit comes in: a breakthrough single-cell long-read sequencing workflow that, as of October 2025, is available exclusively as an Early Access Program through Eremid.
Built on a tuned version of the same PTA chemistry behind ResolveOME1, ResolveSEQ LongRead is specially tuned to generate longer amplicons in the 3.9–4.2 kb range. These amplicons are then processed using Eremid’s custom PacBio library preparation pipeline to assemble 15–20 Kb SMRTbell libraries that are compatible with PacBio Kinnex™ chemistry, before sequencing on the PacBio Revio platform.
This combined workflow delivers exceptional data quality at single-cell resolution:
- 70–92% genome coverage
- >92% phasing accuracy
- 95% positive predictive value (range 91–99%) for SNVs, capturing 97% of all ClinVar SNPs
The result is high-contiguity, haplotype-resolved assemblies that allow detailed analysis of structural variants, copy-number variants, translocations, tandem repeats, and on/off-target edits in individual cells.
Figure 2: How BioSkryb’s ResolveSEQ LongRead platform and Eremid’s long-read sequencing capabilities combine to unlock single-cell long-read sequencing
Starting from the standard kit, our method involves integrating custom library preparation and analysis steps, including stringent QC, deep phasing, and high-contiguity genome assembly pipelines that deliver chromosome-scale insight from each cell. In our benchmark runs across human cell lines, the enhanced workflow produced an average of 83 Gbp of HiFi reads per sample, with contig N50 values exceeding 114 Mb, and low duplication and chimera rates (4–10%).
Brought together, BioSkryb’s tuned PTA chemistry and Eremid’s advanced PacBio technology and expertise set a new standard for single-cell long-read sequencing, combining coverage, phasing accuracy, and structural resolution that surpass any existing method on the market. It marks the first time true long-read single-cell sequencing has been delivered as a service, and enables researchers to:
- DETECT repeat expansions and tandem repeats with accuracy.
- RESOLVE structural variants, translocations, and copy-number changes.
- ASSESS somatic mosaicism in complex or repetitive regions.
- VERIFY genome editing outcomes, including both on- and off-target events.
All from material that was previously too scarce or too fragmented for this level of insight.
Applications and use cases for single-cell multiomics
Single-cell multiomics is a fundamental step change in the depth of analysis and insight that can be gained from a single cell. By linking genomic variation and transcriptional output, technologies like ResolveOME and ResolveSEQ LongRead expose mechanisms that would be invisible with separate assays.
These capabilities are already reshaping research across cancer, neuroscience, cell and gene therapy, and beyond, with exciting possibilities emerging across a variety of research fields
Oncology applications
In acute myeloid leukemia (AML), ResolveOME has been used to follow how resistance emerges in cultured MOLM-13 cells under quizartinib treatment2. In the same cells, researchers detected secondary FLT3 mutations, associated with a high risk of relapse and shorter survival in AML patients, while also capturing the transcriptional rewiring that underpinned cell proliferation. In breast cancer samples, ResolveOME prevented misclassification of contaminating cells and revealed how DNA variants drove oncogenic expression programs, offering a much clearer view of intra-tumor heterogeneity.
Looking ahead, single-cell multiomics has the potential to transform how we monitor clonal evolution, predict therapeutic resistance, and design more precise combination treatments in oncology.
Neuroscience applications
A 2024 Nature study used ResolveOME to study the human forebrain3, where it genotyped mosaic variants while profiling gene expression in the same nuclei. This dual insight provided new evidence for a dorsal neocortical contribution to inhibitory neurons and mapped how clonal dynamics shape cortical architecture. These are insights that would have been invisible without joint DNA and RNA sequencing.
The same approach has the potential to illuminate how somatic mosaicism influences neurodevelopmental disorders, and how rare variants contribute to conditions like epilepsy, autism, or neurodegeneration.
Cell & gene therapy applications
The exceptional genome coverage and phasing accuracy provided by ResolveSEQ LongRead makes it a powerful tool for confirming gene editing results. While short-read methods can flag whether an edit is present, they often miss the context: Was the change correctly phased? Did it alter nearby structural elements? Were there unintended off-target effects?
ResolveSEQ LongRead single-cell multiomics enables researchers to phase large edits, read through repeat expansions or tandem repeats, and confirm on- and off-target CRISPR edits in single cells. For developers of new therapies, that level of resolution is invaluable.
Rare disease research applications
Rare diseases often hinge on events hidden in just a few cells, such as somatic mosaicism or repeat expansions. These are notoriously difficult to detect with short-read sequencing. ResolveSEQ LongRead can resolve complex regions and call structural variants at the single-cell level, supporting discovery in areas that short-read workflows have historically struggled to illuminate.
Immunology applications
The ability to tie genetic variants directly to transcriptional programs in immune cells could be transformative in how we study clonal expansions, immune escape, and variable responses to infection or immunotherapy. ResolveOME’s combination of SNV/CNV detection and full-length transcript capture is well-suited to deliver valuable insights this space.
Agriculture applications
Single-cell multiomics is also poised to make an impact in agriculture science, from tracing genetic drivers of plant traits to profiling microbiomes that influence yield and resilience. Linking genotype to phenotype at the single-cell level offers powerful new ways to accelerate breeding and trait discovery.
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By uniting DNA and RNA in one workflow and unlocking long-read resolution, these technologies reveal mechanisms that would otherwise remain hidden. Whether in cancer, neuroscience, rare disease, or agriculture, the details matter. And now, for the first time, they’re visible.
Bringing clarity to single-cell genomics
The promise of single-cell biology has always been clear: if you can see what’s happening in individual cells, you can understand disease and development at their true resolution. With BioSkryb’s ResolveOME and ResolveSEQ LongRead technologies, that promise is finally being realized — linking DNA and RNA from the same cell, and extending into long-read territory to capture edits, repeats, and complex structural changes with unprecedented accuracy.
As BioSkryb’s only CAP-accredited/CLIA-certified long-read CSP, Eremid is uniquely positioned to deliver these technologies at speed and scale. Through our custom PacBio long-read technology-based workflow and advanced bioinformatics pipelines, we offer researchers the most comprehensive and precise single-cell long-read sequencing available today.
Whether you’re studying cancer heterogeneity, tracing neural lineage, validating cell and gene therapies, or exploring agricultural genomics, Eremid provides the cutting-edge technology and expertise to help you see the signals that matter most.
Get in touch today and explore how Eremid can accelerate your single-cell multiomics projects.
References
- Gonzalez-Pena, V. et al. Accurate genomic variant detection in single cells with primary template-directed amplification. Proceedings of the National Academy of Sciences 118, e2024176118 (2021) doi:10.1073/pnas.2024176118.
- Marks, J. R. et al. Unifying genomics and transcriptomics in single cells with ResolveOME amplification chemistry to illuminate oncogenic and drug resistance mechanisms. bioRxiv 2022.04.29.489440 (2022) doi:10.1101/2022.04.29.489440.
- Chung, C. et al. Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain. Nature 629, 384–392 (2024) doi:10.1038/s41586-024-07292-5.
