Long-Read Genome Sequencing Shows Expanding Diagnostic Value but Faces Cost Barriers

TAIPEI, TAIWAN, Dec. 8th, 2025- Advances in long-read whole-genome sequencing are offering deeper insights into human genetic diversity and rare disease mechanisms, according to new findings presented at a recent international human genetics conference. Multiple research groups shared early results from large, population-scale studies that use long-read technologies to identify variants that are difficult or impossible to detect with traditional short-read methods.

One team presented outcomes from the first phase of a major national research initiative designed to capture genomic diversity across underrepresented communities. In this initial effort, researchers performed long-read sequencing on more than 1,000 participants from genetically diverse backgrounds using a high-fidelity long-read platform at moderate depth. The analysis generated a comprehensive variant catalog, including single-nucleotide variants, small insertions and deletions, structural variants, and repeat expansions.

The project identified nearly one million structural variants, with close to 200,000 of them not previously captured by other sequencing approaches. Among these, almost 500 variants overlapped genes known to influence disease, suggesting potential clinical relevance. Long-read analysis also revealed tandem repeat mutations in medically important genomic regions, including patterns that had been missed in earlier short-read data.

To evaluate the clinical significance of these variants, researchers cross-referenced long-read-derived structural variants with short-read data and electronic health records from an additional 10,000 participants. This phenome-wide association analysis uncovered nearly 300 links between structural variants and health conditions, including cardiovascular disorders. More than half of these associations involved variants not present in short-read data, underscoring the unique resolution offered by long-read sequencing.

While the first phase focused on characterizing variation within one major population group, the ongoing second phase expands the effort to include several additional communities. Early findings from this next phase were also presented, highlighting results from almost 1,500 participants with diverse cultural and genetic backgrounds. These samples were sequenced using multiple long-read platforms to ensure consistency and validation.

The expanded analysis revealed more than 88 million small variants, with roughly 12 percent representing previously unreported changes compared with widely used reference databases. Researchers also detected more than 740,000 structural variants—about 21,000 per genome—and noted that roughly one-third of these are classified as novel. For tandem repeats, over 300,000 genomic regions were examined, resulting in tens of millions of unique repeat sequences.

Population-level analyses further demonstrated extensive genetic diversity, spanning multiple continental ancestries and complex admixture patterns. The team also assessed carrier frequencies for potentially pathogenic variants, identifying more than 400 carriers across the long-read dataset. Additionally, by leveraging long-read technology’s ability to measure DNA methylation, researchers mapped more than 27 million methylation sites and identified nearly 800,000 variable regions, offering a new layer of insight into how genetic and epigenetic factors interact.

Despite growing evidence that long-read sequencing provides richer, clinically relevant genomic information, researchers noted that cost remains a major barrier to large-scale adoption. Funding constraints have already affected the scope of the current project. Even so, the second phase aims to sequence over 12,000 genomes, with data expected to become publicly available in the coming years.

Reference

[1] ASHG: Long-Read Sequencing Elucidates New Variants, Insights for All of Us Program

[2] Population-scale Long-read Sequencing in the All of Us Research Program

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