New Genomic Sequencing Resource Could Improve Care

Analyzing patients’ disease risk by comparing their genome to a reference has become an integral part of treating many cancers, but the technique is limited by current reference genomes being built upon the genetics of a single individual. Recent research outlines the building of a pangenome reference and how it could make sequencing more accurate and effective (Nature 2023;617:312–24).

“The pangenome that we've been building is a representation of germ­line variation across the population. As we expand the pangenome, we will have more and more representation of what's genetically common and it will become increasingly easier to identify germline and somatic variations,” says study co-author Benedict Paten, PhD, of the Genomics Institute at the University of California, Santa Cruz.

“This new tool will allow doctors and researchers to identify when something is unusual or benign across a growing reference of many individuals. This is the application of our research that is going to be impactful in the relatively short term for cancer and for rare disease diagnosis,” continues Paten.

The researchers, who are part of the Human Pangenome Reference Consortium, developed their draft pangenome reference by sequencing and assembling genomes from a diverse cohort of 47 people from around the world. Eventually, the reference will grow to 350 genomes, roughly the number needed to ensure that every genetic variant occurring at a 1% frequency in the human population is included.

The draft pangenome is already proving effective: The researchers report that it increases the number of structural variants detected per haplotype by 104% and reduces small variant discovery errors by 34% compared with the existing GRCh38 reference, which is based on a single genome.

“Breast cancer is the poster child for a malignancy that depends on significant genetic input,” explains Arnold Baskies, MD, of the Rowan School of Medicine in Stratford, NJ, who is not associated with the research. “In particular, there is no clear genetic target for triple-negative breast cancer [TNBC] treatments. A pangenome will give us the ability to identify the mutations that patients with TNBC share. This is a crucial step in zeroing in on therapeutic entry points for personalized treatments and is in contrast to the way we currently treat the disease—with toxic chemotherapy and immunotherapy.”

If pangenomic analysis does indeed allow physicians to identify a specific genetic target for TNBC treatment, it is likely that new, more focused treatments will have fewer side effects, concludes Baskies.

Researchers emphasize that the tools outlined in their article could affect how patients fare as soon as they are more widely adopted. “The most significant limitation to getting these methods into the hands of clinicians is one of education. We simply need more clinicians to be aware of these approaches and their power,” says study co-author Erik Garrison, PhD, of the University of Tennessee Health Science Center in Memphis.

For now, pangenomic sequencing is being harnessed to identify germline and somatic variation, but single-molecule sequencing, like that used to build the pangenome, gives researchers the ability to read epigenetic marks directly.

“Combining the pangenome with epigenetic data could provide a key reference resource for clinical applications that can provide perspective on how typical certain epigenetic patterns are in the population,” explains Garrison. “Although the current pangenome doesn't directly represent epigenetic patterns, our data supports this, and we will be working on ways to integrate the pangenome with epigenetic information in subsequent phases of the pangenome project.” –Myles Starr

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