This week PacBio is bringing our energy and innovation in human genomics to ASHG in Boston, and there’s no better time to learn about what we’ve been up to.
Join us at booth #919 to meet our scientists, see live demos of Revio and Vega, and catch our sessions throughout the week to hear how PacBio HiFi sequencing is helping researchers explore the full spectrum of human genomic diversity.
As we share our advances with researchers at ASHG, that same vision to see the whole picture is coming to life in recent publications. A key example is in a new study from the All of Us Research Program (AoU). Powered by PacBio HiFi technology, this study is the first AoU large-scale, population-level analysis using long-read sequencing…and the results are striking.
Researchers found that standard short-read sequencing only detected half of disease-associated structural variants in their cohort. This revelation shows just how much of the human genome has remained out of view until now and fundamentally redefines what it means to truly “see everything” in the human genome.
The power of All of Us
The NIH-funded All of Us Research Program is set to amass longitudinal health data and genome sequences of 1 million U.S. participants with the goal of advancing precision medicine research and fueling new insights into human health. With what will become one of the largest, most comprehensive, and most broadly accessible datasets ever assembled, the All of Us program is designed to reflect the true diversity of the United States with a specific recruitment emphasis on individuals from groups whose health outcomes remain understudied.
This study represents Phase 1 of the program and uses HiFi sequencing to analyze the genomes of 1,027 individuals self-identifying as Black or African American, with later phases expanding sequencing more broadly across the population.
Uncovering the hidden half of the genome
From this data at around 8× HiFi coverage, the team built one of the most comprehensive catalogs of genetic variation to date, spanning single-nucleotide variants, indels, repeat expansions, and, most importantly, structural variants (SVs). Performing a phenome-wide association (pheWAS) study, the researchers then imputed these HiFi-based SVs into a short-read WGS dataset of over 10,000 individuals (also self-reported as Black or African American) with matched electronic health record phenotype data. Across this dataset, the authors found 291 structural variants associated with disease, covering 226 conditions.
Most remarkably, more than half of these disease-associated structural variants were absent from matched short-read data, and in 70% of the pheWAS disease loci, the structural variants found by HiFi were found to drive the strongest association.
In other words, short reads captured only half the picture when it comes to identifying variants associated with disease.
Revealing the variants short reads leave behind
This study is a turning point for human genomics. It shows that much of what drives disease lies not in the small changes that are visible with short reads, but in the larger structural changes completely invisible to this technology.
In part of this study, AoU researchers also uncovered 273 previously unknown SVs that overlapped hundreds of medically relevant genes, including several tied to disease risk, cancer predisposition, and pharmacogenomics.
Many of these variants found in genes associated with inherited or complex diseases show specific ties to genomes of African genetic ancestry, like APOB and MYH7, which are linked to cardiovascular disease. Broadening these discoveries across populations shows how long-read sequencing can fundamentally change what we can know about human health.
In a critical addition only possible with HiFi sequencing, the team also resolved known and previously unseen repeat expansions and complex regions. In a case where the researchers identified four pre-mutation alleles in FMR1, the gene associated with Fragile X syndrome, this finding was corroborated by the health records describing a child with FXS-consistent symptoms.
This connection from HiFi data to phenotypic insights clearly shows the potential of HiFi sequencing to turn genomic discovery into impactful understanding of human disease.
A more representative picture of human health
This first phase of AoU’s long-read initiative focused deliberately on participants who are least represented in genomic databases in an effort to achieve more complete and representative biobank data.
HiFi long-read sequencing makes this finally possible.
In this cohort, 58% of identified SVs were more frequent in African genetic ancestry, and thousands of variants were specific to those populations. By illuminating previously hidden variation and extending across populations in later phases of the project, this work helps ensure that the foundation of precision medicine includes everyone it intends to serve. As Phase 1, this already groundbreaking study is quite literally just the beginning.
We are excited by what this work means for genomics research. HiFi sequencing has proven essential for capturing the complete genetic architecture underlying human disease and the information it provides can be critical to therapeutic development and the future of human health.
Comprehensive, inclusive precision medicine requires comprehensive, inclusive sequencing that captures the genomic diversity within all of us.
To explore the technology powering these breakthroughs in real time, visit us this week at ASHG 2025 and discover how HiFi sequencing is helping the world see the whole story.