AGRF Pulse I Why Long Read Sequencing Is Becoming the Benchmark for Human Whole Genome Sequencing

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Pictured: Dr Lucas Trevisan, Molecular Scientist in our Long-Read Sequencing Department, preparing a WGS HiFi library at our Brisbane laboratory.

Well, there are just some things that short-read sequencing simply can't do.

Long‑read sequencing is now the tool to deliver high confidence, comprehensive human whole genome sequencing (WGS). At AGRF, long-read technologies, including both PacBio HiFi and Oxford Nanopore, have become essential for researchers who need accuracy, completeness, structural resolution, and confidence across all genomic regions. Let’s be honest, there are regions in the human genome that short reads struggle to resolve.

While multiple platforms now support long‑read sequencing, PacBio HiFi has emerged as the benchmark for human WGS due to its combination of long reads and exceptionally low error rates.

 

Long-read vs short-read in genome mapping. Longer read length enhances alignment accuracy.

 

Why Long‑Read Matters: Quality, Completeness, and Context

Unmatched Accuracy

Long-read sequencing has historically required a trade-off: length vs accuracy. Modern long-read platforms, especially PacBio HiFi, have closed this gap. HiFi reads consistently achieve Q30–Q40 accuracy, with many datasets exceeding >Q35. Together with the typical HiFi read lengths of 10–25 kb, a long-range single-molecule sequencing has contributed some of the most important breakthrough in human genomics:

  • resolve GC rich and repetitive regions

  • detect structural variants with confidence

  • phase haplotypes across large genomic distances

  • epigenetics investigations such as DNA methylation, chromatin accessibility, and nucleosome positioning

This results in a more complete and biologically meaningful representation of the human genome.

 

Correlation between read length and bases accuracy in different sequencing platforms.

 

Beyond Genomes: Full-Length Transcriptome Sequencing

Long read sequencing becomes even more powerful when combined with IsoSeq, which captures full length RNA isoforms without assembly. This allows for:

  • preservation of complete isoform structures

  • characterisation of alternative splicing, transcript diversity, and gene models

  • high confidence gene annotation.

Together, HiFi genomes and IsoSeq transcriptomes offer deep biological insight across human health, agriculture, wildlife, and non-model organisms.

Advantages that PacBio HiFi WGS and Iso-seq offers.

Growing Adoption Across Clinical and Research Applications

With a powerful tool to unpack human genomics, Long‑read sequencing is now widely used in:

  • Population genomics

  • Rare disease diagnostics

  • Cancer research

  • Pharmacogenomics

  • Development of clinical reference standards

Its balance of accuracy, read length, and coverage makes long‑read sequencing one of the most trusted technologies for translational and clinical genomics.

 

Pacbio technologies, HiFi WGS, Fiber-Seq and Iso-Seq, allows a much deeper biological understanding of human genetics.

 

As AGRF’s Innovation and Development Scientist, Dr Angus Li notes,

“PacBio HiFi sequencing uniquely combines long-read lengths with high accuracy, enabling analyses that simply aren’t achievable with other platforms.”

Supporting Advanced Genomics in Australia

As a national genomics provider, AGRF ensures researchers across academia, government, industry, and clinical sectors have access to high‑quality long‑read sequencing, expert scientific support, and bioinformatic analysis.

Long‑read sequencing, led by PacBio HiFi as the benchmark, has become essential for answering complex genomic questions. AGRF is committed to helping Australian researchers harness its full potential across health, agriculture, and environmental sciences.

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Prepared by Louise George Senior Communications Specialist, content developed by Marie Everest Technical Support Specialist and Desley Pitcher Head of Strategic Business. Illustrations created by / content reviewed by Angus Li Innovation and Development Scientist at AGRF. *Illustrations are AI adapted.