Ultima’s ppmSeq Pushes Sequencing to New Levels of Accuracy

By Bio-IT World Staff  

August 28, 2025 | Ultima Genomics unveiled updates on the single-nucleotide variant (SNV) detection capabilities of its plus-minus sequencing (ppmSeq) technology, which were published at bioRxiv (DOI: 10.1101/2025.08.11.669689). The updates elaborate beyond the limits of currently available minimal residual disease assays. 

According to the authors of the paper, state-of-the-art molecular de-noising approaches for DNA sequencing rely on duplex sequencing, where both strands of a single DNA molecule are sequenced to discern true variants from errors arising from single stranded DNA damage. However, these duplex approaches “typically require massive over-sequencing to overcome low capture rates of duplex molecules.” 

Conventional duplex sequencing methods try to suppress errors by sequencing both strands of a DNA molecule independently and comparing them. While powerful, this method comes at a high cost: massive over-sequencing is required to capture enough usable duplex molecules, driving up expense and complexity. 

“With its unique combination of low-cost and high accuracy, ppmSeq marks a real breakthrough in sequencing technology,” said senior author and lead researcher Dan A. Landau, MD, PhD, a core member of the New York Genome Center and Professor of Medicine & Professor of Physiology and Biophysics at Weill Cornell Medicine lab at the New York Genome Center. 

Instead of treating the DNA strands separately, Ultima’s ppmSeq partitions and clonally amplifies both strands together on sequencing beads using emulsion PCR. The result is a single sequencing read that inherently carries information from both strands, enabling duplex-level accuracy that scales naturally with sequencing depth.  

According to the preprint, the Landau team used Ultima’s ppmSeq to further improve upon the SNV detection limits. The ppmSeq achieved up to part-per-ten million (107) accuracy (SNVQ70) for SNV calling, and it does so with 10- to 100-fold less sequencing than competing error-correction strategies. For a field where cost remains one of the biggest barriers to widespread adoption, that efficiency could be game-changing. 

The ppmSeq’s applications are in oncology, where circulating tumor DNA (ctDNA) offers a minimally invasive way to monitor disease. Today’s best minimal residual disease (MRD) assays can typically detect one mutant molecule in 100,000. Ultima reports ppmSeq can go much further: down to one in 10 million in cancers with high mutation burdens. That level of sensitivity opens up the possibility of spotting recurrence earlier, tracking tumor evolution in real time, and even detecting cancer in its earliest, most treatable stages. 

However, the authors noted that ppmSeq is not without limitations. Because the method relies on hydrogen bonding in its emulsion chemistry, it is currently only capable of whole-genome assays. Its error rates are slightly higher than those of classical duplex sequencing, though offset by significantly higher recovery rates and efficiency. “The tradeoff between error rate and yield is therefore an important consideration and is likely to be application dependent.” 

Nonetheless, ppmSeq proves great potential for genomics’ next steps. For biotech developers, investors, and clinicians alike, ppmSeq signifies that the cost–accuracy trade-off that has long defined sequencing may finally be breaking.