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How SPRQ Chemistry Is Breaking Barriers in DNA Sequencing

Illuminated ATGC letters in blue squares representing next-generation sequencing.
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Advancements in DNA sequencing technology have revolutionized genomics research, enabling scientists to unravel the genetic drivers of complex diseases and broaden our understanding of genetic diversity. Long-read sequencing technologies have emerged as powerful tools, yet challenges such as high costs, sample input requirements and scalability have hindered widespread adoption in large-scale studies and clinical applications.


PacBio’s newly launched SPRQ chemistry aims to address these challenges by delivering groundbreaking improvements in sequencing efficiency and accuracy, reducing the cost of sequencing a human genome to under $500.


To learn more about SPRQ chemistry, Technology Networks recently spoke with Dr. Aaron Wenger, senior director of product management at PacBio. In this interview, Wenger highlights the technology's unique benefits, its role in expanding our understanding of rare diseases and the ongoing efforts to make HiFi sequencing more accessible to researchers and clinicians worldwide.


Anna MacDonald (AM):
Can you give us an overview of the new SPRQ chemistry and the benefits it can bring to researchers?

Aaron Wenger, PhD (AW):
The SPRQ chemistry brings three major benefits: 4x lower DNA input, 33% higher sequencing yield and more accurate direct methylation detection. With only 500 ng of DNA needed for a human whole genome, HiFi sequencing is now accessible for challenging samples like saliva, tumors, neonates and small organisms. The increased yield enables sequencing of two human genomes per SMRT Cell, reducing costs to $500 per human genome and boosting system throughput to 2,500 human genomes annually. The enhanced methylation accuracy makes HiFi sequencing a strong alternative to methylation microarrays, eliminating the need for separate workflows and costs.

SPRQ is PacBio’s most transformative chemistry since the launch of HiFi sequencing in 2019. It is the result of groundbreaking advancements in surface chemistry and polymerase engineering. By optimizing DNA behavior on the SMRT Cell and refining loading reagents and workflows, we’ve maximized the efficiency of DNA loading. Meanwhile, extensive polymerase screening led to a more processive and accurate polymerase, producing higher-quality HiFi reads.


AM:
Reducing the cost of a HiFi human genome to under $500 is a major milestone. How might this price reduction accelerate large-scale genomic studies and what impact could this have on our understanding of complex diseases and their genetic underpinnings?

AW:
Since the release of the Revio system in 2023, HiFi sequencing has powered large-scale studies such as All of Us in the United States, the Estonia Biobank in Europe and PRECISE in Singapore. It’s also become a key tool in rare disease networks like GREGoR, enabling these projects to analyze the full genome – including structural variants, tandem repeats, hard-to-sequence genes like SMN1/2 and DNA methylation patterns. HiFi sequencing has also facilitated the development of pangenomes, which capture genetic diversity across global populations rather than relying on a single reference genome.

The reduced cost and increased throughput enabled by SPRQ chemistry will allow these projects – and new ones – to expand their sample sizes. This will deepen the scientific community’s collective understanding of genomic features like tandem repeats, structural variants and methylation that play critical roles in complex diseases but have been more challenging to study than single-nucleotide variants.


AM:
What unique advantages does HiFi sequencing offer in helping diagnose rare diseases compared to traditional short-read sequencing? How might these advantages impact patient outcomes and treatment options?

AW:
HiFi sequencing provides an exceptional view of genetic and epigenetic variation, all from a single assay. Rare diseases are often driven by a few key genetic or epigenetic changes and HiFi sequencing reveals variations in genomic regions that short-read technologies miss. Crucially, it also identifies variation in phase, enabling scientists to analyze maternal and paternal genomes separately.

Institutes around the world, including Children’s Mercy Kansas City, HudsonAlpha and Radboud University have shown that HiFi sequencing detects pathogenic variants missed by other technologies in about 10% of cases. These discoveries help pinpoint the genetic cause of rare diseases, opening the door to targeted treatments and improved outcomes.


AM:
What are some of the key logistical and technical challenges you foresee in implementing HiFi sequencing broadly across clinical settings for rare disease genomics? What approaches are being taken to overcome these barriers? 

AW:
Broad adoption of HiFi sequencing requires seamless, end-to-end workflows – from DNA extraction to data interpretation. To streamline upstream processes, we’ve partnered with PacBio Compatible Partners to automate DNA extraction, shearing and library preparation. This has significantly lowered costs and improved scalability. Recent advancements, such as support for saliva samples, are broadening sample compatibility.

Data processing is another hurdle. We’ve addressed this with standardized workflows like the HiFi WGS variant pipeline, available both locally and on the cloud. The cloud-based SMRT Link software and improved connectivity in our sequencers simplify data transfer and processing.

Lastly, building comprehensive databases of genetic variation is critical for interpreting results. HiFi sequencing identifies more variation than previous technologies, making it vital to expand reference datasets. Through initiatives like CoLoRS and HiFi Solves, PacBio is collaborating with global partners to develop these essential resources.


AM:
Looking ahead, are there other features that PacBio is exploring to add to its sequencing systems?

AW:
Beyond whole-genome sequencing, HiFi technology is revolutionizing RNA research by providing a complete view of RNA isoforms. We’re enhancing our RNA-sequencing capabilities with tools like the Kinnex full-length RNA kit and plan to improve on-instrument data processing for these applications.

We’re also expanding our PureTarget portfolio, which uses Cas9 and guide RNAs to enrich specific genomic regions. This allows cost-effective, high-coverage sequencing of native DNA molecules in targeted regions.

Finally, we’re committed to making PacBio sequencers even more user-friendly, with advancements in interfaces, user authentication and logging systems. These improvements will ensure a seamless and secure experience for researchers.