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The dual benefits of population-scale genomics

Once expensive and cumbersome, population-scale exome sequencing is becoming a public health tool.Credit: Tetiana Lazunova / iStock / Getty Images

Science is perpetually evolving, but certain inflection points stand out. In the 1970s, Fred Sanger and his team at the Medical Research Council Laboratory of Molecular Biology, in the United Kingdom, introduced a new method of DNA sequencing, which enabled small runs of DNA to be read in succession. The development of that technique, now known as Sanger sequencing, launched a long period of discovery. Positional cloning and other basic research techniques laid the foundation for the clinical panels that now guide diagnosis and disease management.

With the refinement and reduced cost of sequencing technology, science has reached another inflection point: population-scale genomics, where clinical-grade assays can be used to advance healthcare, while fueling research.

The Healthy Nevada Project (HNP) epitomizes that movement. A population health initiative run by the Renown Institute for Health Innovation (Renown IHI), a partnership between Renown Health and the Desert Research Institute, the project aims to combine genomic, environmental and medical data from 250,000 participants to assess the influence of genetics on health and disease. The study also uses sequencing data to screen participants for medically actionable genetic conditions, such as familial hypercholesterolemia (FH), hereditary breast and ovarian cancer syndrome (HBOC), and Lynch syndrome (LS).

Working with scientists at Helix, the Healthy Nevada Project has recruited more than 25,000 study participants.Credit: Helix

To reach its goals, Renown IHI has partnered with Helix, a population genomics company. Helix provides a combination of services that permits the collection of genetic data on a population scale. Each study participant is sequenced using Helix’s proprietary Exome+® ssay, which provides coverage of the entire exome as well as 300,000 locations outside protein coding regions. In contrast to microarray technology, the Exome+® assay combines DNA sequencing with custom bioinformatics pipelines. Together, these enable broader use of genomic data, including the analysis of clinically validated copy number variants, genome-wide imputation of tens of millions of high-confidence SNPs, and the discovery of rare variant effects. When designing the Exome+® assay, Helix also boosted coverage of medically relevant regions to enable clinical-grade data that may influence a participant’s healthcare.

This work has already generated a useful pool of data. Helix and the HNP are gathering insights about disease penetrance in unselected populations, the potential impacts of broader screening guidelines, and novel gene-phenotype associations. The project is also returning results to participants who show a predisposition to those conditions.

In July, Helix and the HNP team reported findings from the first 27,000 participants in an article published in Nature Medicine1. Among HNP participants, the researchers found that approximately 1 in 75 carried a variant predisposing them to HBOC, LS, or FH. Of those predisposed, nearly 22 percent had already begun to develop symptoms of disease. Importantly, 90 percent of those with medically actionable results would not have known about their increased risks for disease had they not participated in the study; patients often don’t qualify for genetic screening under current clinical guidelines.

Participants in the Healthy Nevada Project register before giving over a saliva sample which can be sequenced.Credit: Healthy Nevada Project

The HNP is aiming to reach more than 250,000 Nevadans. Ongoing collaboration between Helix and the HNP team has produced novel gene-phenotype associations which were recently published in Nature Communications2, and the world’s largest database of mitochondrial variations (pre-print available here).

Similar projects that serve both research and public health are underway elsewhere. The WholeMe study in Florida is run as a partnership between AdventHealth and Helix. As in the Healthy Nevada Project, WholeMe study participants are sequenced using Helix’s Exome+® assay and subsequently screened for genetic variants associated with FH.

While the number of these large-scale projects is still low, it has grown rapidly in the past year and will likely continue to do so. Assays such as Helix’s Exome+® assay enable researchers to influence both healthcare and research with a single project, and do so at large scales and permissible costs.

To learn more about exome sequencing and population genomics, visit Helix.

References

  1. 1.

    Grzymski, J.J., Elhanan, G., Morales Rosado, J.A. et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med (2020). https://doi.org/10.1038/s41591-020-0982-5

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    Cirulli, E.T., White, S., Read, R.W. et al. Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts. Nat Commun 11, 542 (2020). https://doi.org/10.1038/s41467-020-14288-y

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