November 7, 2025 | Powered by PacBio

This month’s roundup showcases the diverse ways researchers are using PacBio technology to uncover new insights across population genomics, cancer research, neurodegenerative disease, and precision medicine. In the October 2025 edition of Powered by PacBio, we highlight an outstanding analysis of structural variants in the All of Us Research Program, new findings on somatic mosaicism in Fragile X–associated syndromes using the PureTarget panel, a multi-tech exploration of telomere-to-telomere mutation burden in cancer, and a forward-looking review of ALS research that reinforces the role of long reads in supporting gene therapy development.

Across these studies, long-read sequencing enables discoveries that short-read methods miss, delivering more complete variant profiles, resolving epigenetic complexity, and building individualized reference frameworks that better reflect real-world diversity.

Jump to topic:

Population genomics | PureTarget | Cancer Research | Biopharma

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Population-scale long-read sequencing in the All of Us Research Program

In this preprint, researchers from AoU NIH, UW, Broad, Mass General, Harvard, JHU, U MN, U Miami, Mayo, U Pittsburgh, DLS AL, Baylor, and Vanderbilt complete “the first large-scale analyses of long-read sequencing (LRS) in AoU [All of Us],” resulting in “a new framework for deriving genomic insights into complex structural variation (SV) of relevance to human health and disease.”

Key highlights:

• Joint analyses of 1,027 individuals (self-identifying as Black or African American, ~8x HiFi coverage per sample) formed the basis of this Phase 1 study, which will be expanded in Phase 2 to include broader population representation.
• Researchers generated a comprehensive variant callset of known and novel repeat expansions, clinically relevant haplotypes at loci inaccessible to srWGS, and haplotypes relevant to disease risk and pharmacogenomics, including SNVs, indels, and SVs.
• Among the findings were “273 high-priority, previously unreported SVs,” including 172 that “overlapped 170 medically relevant genes,” 73 intersecting “69 high-priority disease related genes”, and 15 affecting “14 genes associated with cancer risk.” These SVs represent “compelling candidates for studying disease risk, especially in individuals of African genetic ancestry.”
• In total, the team identified 291 SV-disease associations spanning 226 conditions, with “50.9% of associations involving SVs absent from the matched srWGS callset”.
• Looking deeper, they found “191 SV-disease pairs spanning 160 traits (70.8%) where the SV had the strongest association within the locus,” consistent with “high-risk, ancestry-specific variants.”
• The authors found that “These results demonstrate that the integration of LRS into AoU and future biobank initiatives can provide transformative new insights into genomic variation with potentially profound impact on precision medicine.”

Conclusion:

This landmark preprint leaves no doubt: structural variants (SVs) are central to understanding human disease. Half of all disease associations uncovered were tied to SVs completely missed by short-read methods, reinforcing that it’s SVs, not nearby SNPs, driving these signals. Given these findings, it’s important for future population genomics projects to incorporate PacBio long-read sequencing.

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Long-read sequencing reveals extensive FMR1somatic mosaicism in Fragile-X associated tremor/ataxia syndrome in human brain

In this preprint, researchers from U CO and UC Davis) find that “long-read sequencing is superior for interrogation of somatic mosaicism.”

Key highlights:

• FXTAS and Fragile X syndrome are progressive neurodegenerative disorders caused by a CGG repeat expansion in the 5’-UTR of FMR1. “Although the CGG repeat tract is known for instability that has been posited to contribute to clinical heterogeneity, the extent of somatic variation in human brain remains unclear, in part due to the technical limitations of sequencing long tandem repeats.”
• Using PacBio’s PureTarget amplification-free panel, researchers uncovered “remarkable somatic mosaicism in repeat size and methylation in FXTAS, including somatic expansions and contractions which were not resolvable with traditional approaches”, and “also identified unexpected patterns of methylation mosaicism on pre and full mutations.”
• The study further revealed that “low frequency changes, including somatic expansions, contractions, and methylation alterations were frequently undetected with TP-PCR/CE that long-read sequencing easily distinguished.”
• Expanding their analysis, researchers examined “expansions in 19 additional disease-associated repeat loci” and found “additional expansions in 5 out of 8 affected individuals, in FXN and RFC1.”
• Overall, the authors emphasize “the potential of long-read sequencing to advance our fundamental understanding of somatic mosaicism of these intractable regions of our genome.”

Conclusion:

This new panel goes beyond long repeat detection to capture complex methylation patterns that traditional technologies, including short reads, often miss entirely. By providing deeper insights into conditions like Fragile X and ataxia syndromes, PureTarget empowers researchers to streamline multiple assays into a single workflow, making it easier to study genetically complex neurodegenerative disorders.

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A telomere-to-telomere map of somatic mutation burden and functional impact in cancer

In this study, the SMaHT consortium, led by UW “[provides] a new standard for somatic mutation characterization in precision cancer genomics.”

Key highlights:

• Researchers used a multi-tech approach to generate diploid, near-T2T donor-specific assembly (DSA) described as “an accurate and complete representation of the germline genome”. They then overlaid cancer sample data onto “a donor-specific graph genome (DSG) containing the COLO829BL DSA, GRCh38, and CHM13” to transfer reads and variant calls between the two COLO829BL haplotypes and GRCh38.
• They found that “16% of somatic variants occur in sequences absent from GRCh38,” especially in satellite repeat regions prone to “UV-induced damage due to sequence-intrinsic mutability and inefficient repair.” These findings suggest that “GRCh38-based somatic variant catalogs systematically underrepresent the true extent of somatic variation that exists in a sample.”
• “Centromere kinetochore domains emerged as focal sites of structural, genetic, and epigenetic variation,” highlighting ongoing “remodeling of centromere kinetochore binding domains during tumor evolution.”
• The team also performed “**single-molecule telomere reconstructions” **that revealed dynamic cycles of “**attrition, deletion, and telomerase-mediated extension **that shape cancer telomeres.”
• “Diploid [Fiber-seq] chromatin maps” revealed that copy number alterations and epimutations, rather than point mutations, play a dominant role in “rewiring cancer regulatory programs,” with the study noting that **“only 0.02% of sSNVs” **had a direct observable impact on the chromatin epigenome.
• “By integrating long-read sequencing, diploid assembly, single-molecule chromatin fiber sequencing, and graph genomes, we overcome the limitations of incomplete references such as GRCh38, CHM13, and reference pangenomes. This framework enables somatic variants to be defined directly within the context of an individual’s genome.”

Conclusion:

This preprint changes the game, demonstrating that many disease-driving changes aren’t SNPs, but complex variants in regions that short-read methods simply can’t access. While multiple technologies contributed, PacBio was central to the study, showcasing the full power of our multiomic toolkit: HiFi WGS, methylation, Fiber-seq, and Kinnex RNA. It’s a landmark moment for cancer genomics, and for precision medicine built on complete, individual reference maps.

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Entering the era of precision medicine to treat amyotrophic lateral sclerosis

In this preprint, researchers from Australia and the UK conclude that “Long-read sequencing will revolutionise our understanding of ALS genetics through the comprehensive mapping of genetic variation.”

Key highlights:

• This study showcases the complex, heterogenous genetics and pathology of ALS, including diverse variant classifications, gene types, population genetics data, and links to other neurodegenerative conditions. The paper positions this complexity within the context of precision medicine, including antisense oligo and gene therapy development.
• Stressing limitations of short-read sequencing that have hampered ALS research, the authors note a “**skewed picture of genomes **focused on SNVs, Indels and CNVs (copy number variations), but being challenged in resolving other genomic features.”
• A dedicated chapter (with 53 references) outlines how PacBio “demonstrated superior performance in sequencing genomes”, spanning HiFi capabilities in SVs, segmental duplications, tandem repeats, complex regions, haplotype phasing, methylation, full-length RNA sequencing, and synchronous multiomics.
• The study includes a description of PacBio use in ALS research to date, highlighting five additional “examples for genetic answers in CNS diseases unlocked through HiFi long-read sequencing.”
• “With the emergence and increased accuracy of long-read sequencing technology it is now evident that all ALS patients should be offered whole-genome sequencing and that the current gaps in our understanding will continue to be filled as the genomes of ALS patients from varying ethnicities are sequenced and studied. ALS genetic architecture clearly differs between ethnic populations and the global efforts to establish improved, and population specific reference genomes will assist in the understanding of genetic drivers of disease in each specific patient group. This will not only enable a better understanding of the drivers of disease but will also allow the design of population specific treatments that encompass a true precision medicine approach.”

Conclusion:

This review adds to a growing wave of papers positioning PacBio at the center of neurodegenerative disease research. It highlights why programs like Target ALS are turning to HiFi sequencing to tackle the genomic complexity that short reads leave behind. With the power to resolve structural variants, repeats, methylation, and full-length transcripts in a single workflow, PacBio gives researchers the complete picture they’ve been missing and moves the field closer to real breakthroughs in ALS research.

Ready to make discoveries of your own?

As October’s roundup makes clear, long-read sequencing continues to power research that is both broader in scope and deeper in resolution. From uncovering population-scale SVs in historically underrepresented communities, to enabling truly complete maps of cancer and neurodegenerative genomes, the studies featured this month demonstrate the growing impact of PacBio’s multiomic tools. These capabilities are helping researchers push past the limits of reference bias and short-read blind spots and moving science closer to more precise answers, more inclusive discoveries, and more personalized care.

Stay tuned for next month’s round-up of recent publications using PacBio technology.

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