For decades—perhaps since 1953 when James Watson and Francis Crick unraveled the structure of DNA, thanks in good part to the work of Rosalind Franklin—scientists expected genomic information to impact healthcare. In addition to improving healthcare when someone is sick, clinicians hope that information about a person’s DNA will impact everyday circumstances, such as guiding preventive medicine in a very precise way for one person. With seemingly constant improvements in whole-genome sequencing (WGS)—from reagents and sample preparation through sequencing platforms and data analysis—making genomics a common clinical tool might not be far away.
In 2013, the 60th birthday of the structural determination of DNA, researchers from the Baylor College of Medicine wrote that the “increased availability of an individual’s genetic information may provide a useful tool for the practicing physician, eventually assisting in differential diagnosis and potentially enabling anticipatory guidance and possibly preventive genomic medicine.”
Already, WGS benefits many clinical studies. Scientists in Denmark, for example, applied WGS to Campylobacter jejuni—a bacterium that causes gastroenteritis—to explore antimicrobial resistance. These researchers reported: “we found that WGS can predict antimicrobial resistance with a high degree of accuracy and have the potential to be a powerful tool for AMR surveillance.”
Other clinical applications exist, as well. “Perhaps the most interesting uses of sequencing in clinical labs include expanding the footprint of cancer diagnostics, particularly for understanding the genetic underpinnings of cancer and informing potential treatments with companion diagnostics,” says Jonathan Jacobs, senior director of bioinformatics for the American Type Culture Collection (ATCC). “Also, from an inherited disease perspective, whole-genome sequencing may reveal other risk factors and may inform potential treatments.”
One example example of using WGS in cancer research comes from a team of scientists in Sweden. These researchers studied high-risk neuroblastomas and revealed a molecular mechanism that could contribute to the growth of these cancers.
Clinicians can also use WGS to dig into the details of diseases. “One of the most interesting clinical applications of WGS is rare-disease diagnosis for which WGS provides an unbiased approach to detect the genetic changes that cause disease,” says Aaron Wenger, principal scientist at PacBio. “WGS provides diagnoses for more cases, and with a faster turnaround time, than serial single-gene testing.”
As the turnaround time gets even faster, and the process and cost of WGS gets easier and less expensive, even more clinical applications should become possible.
Obstacles to overcome
Even though WGS keeps improving, more advances would make it even more useful, especially in the clinic. “A key challenge for clinical WGS is that it currently relies on short-read sequencing, which—although it detects many variants—is not comprehensive,” Wenger explains. “Structural variants and small variants in difficult-to-map regions are not detected well by short-reads.” To get at those classes of variants, scientists need to add secondary assays like deletion/duplication arrays or targeted gene testing. “It also remains a challenge to interpret these difficult variants since they are not well represented in the large databases of variation in the human population that were built with short-read sequencing.”
Platforms that sequence long reads, such as the Sequel Ile, can detect some variants that are missed in short-length sequencing. Image courtesy of PacBio
For longer reads, some options already exist. “PacBio HiFi sequencing, which produces reads that are both accurate and long, provides a more accurate and comprehensive view of variation than short-read sequencing,” Wenger says. “HiFi sequencing is able to detect the single-nucleotide variants and indels found by short-read sequencing plus structural variants and variants in difficult-to-map regions.” With this technology, scientists only need to run one assay. Plus, Wenger notes that “scientists have applied HiFi reads successfully in cases where exome sequencing or even short-read whole genome sequencing failed to provide answers.”
It’s not just the technology that will improve the ability to apply WGS in the clinic. Researchers also need more data. As Wenger points out: “We need larger cohorts of individuals sequenced with long reads, including more population-specific reference genomes to improve variant interpretation.”
Creating a collection
If anyone knows about collecting data, it’s ATCC experts. “ATCC has a significant collection of materials that can drive and impact drug discovery and infectious disease diagnostics, and WGS provides insight and informs researchers on important factors relevant for clinical outcomes,” says Jacobs.
As part of ATCC’s Enhanced Authentication Initiative, the organization developed the ATCC Genome Portal to help customers easily access and analyze reference-quality genomes and supporting metadata that are tied back to extensively characterized and authenticated biological materials. As Jacobs explains, “Customers can easily access and download our gold-standard whole-genome sequences, and they also will see annotations and referenced data.”
The key from ATCC is accuracy. “ATCC has hundreds of thousands of products, and the accuracy and the availability of genomic data is extremely important,” Jacobs says. “There is so much genomic data out there that everyone assumes is correct, but it may be inaccurate, incomplete, or outdated.” Those are precisely the problems that ATCC addresses.
As Jacobs describes it: “With the ATCC Genome Portal, we provide an ever-expanding, comprehensive, high-quality reference database for clinicians and basic researchers to accurately interpret genomic results and make insightful correlations.”
Coming to the clinic
Even as the technology progresses, other aspects of the healthcare community must also improve. As Wenger notes, “There remains a need for more awareness among physicians about how and when to request sequencing and reimbursement to cover the process so it can be used for a broader range of clinical applications.”
Despite the challenges, Wenger remains optimistic. He believes that generating more genomic data “will allow us to improve interpretation based on a more solid data foundation.” He adds, “It will also give us more success stories that could help convince payers of clinical utility and get the word out to more physicians about how this may benefit their patients.”
As shown here, it takes an entire healthcare community—from patients and physicians through scientists and insurers—to get the most out of WGS in the clinic. Also, it takes time to get all of these players working together.