The original reference human genome sequence, now almost two decades old, is limited in its representation of the diversity of the human species as it consists of genomes from only about 20 people, and most of the reference sequence is from only one person.

Now, researchers have captured substantially more diversity from different human populations than what was previously available by releasing a new, high-quality, collection of reference human genome sequences. The work was led by the international Human Pangenome Reference Consortium, a group funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH).

The new pangenome reference includes genome sequences of 47 people (with the researchers pursuing the goal of increasing that number to 350 by mid-2024) containing 94 distinct genome sequences—with a goal of reaching 700 distinct genome sequences by the completion of the project.

The work, appearing in the journal Nature, entitled, “A draft human pangenome reference,” is one of several papers published by consortium members.

“The new reference information is much richer and improves our ability to analyze human genomes for the purposes of drug discovery, disease diagnosis, and genome-guided precision medicine,” said Ira Hall, PhD, professor of genetics at Yale School of Medicine and director of the Yale Center for Genomic Health.

Using advanced computational techniques to align the various genome sequences, the researchers constructed a new human pangenome reference with each assembly in the pangenome covering more than 99% of the expected sequence with more than 99% accuracy.

The new pangenome reference is a collection of different genomes from which to compare an individual genome sequence. Like a map of the subway system, the pangenome graph has many possible routes for a sequence to take, represented by the different colors. [Darryl Leja, NHGRI]
“By using the pangenome reference, we can more accurately identify larger genomic variants called structural variants,” said Mobin Asri, a graduate student at the University of California Santa Cruz. “We are able to find variants that were not identified using previous methods that depend on linear reference sequences.”

The total cost of supporting the work of the Human Pangenome Reference Consortium is projected to be about $40 million over five years, which includes efforts to create the human pangenome reference, improve DNA sequencing technology, operate a coordinating center, conduct outreach and create resources for the research community to use the pangenome reference.

“Basic researchers and clinicians who use genomics need access to a reference sequence that reflects the remarkable diversity of the human population. This will help make the reference useful for all people, thereby helping to reduce the chances of propagating health disparities,” said Eric Green, MD, PhD, NHGRI director. “Creating and enhancing a human pangenome reference aligns with NHGRI’s goal of striving for global diversity in all aspects of genomics research, which is crucial to advance genomic knowledge and implement genomic medicine in an equitable way.”

In line with this effort, the Human Pangenome Reference Consortium includes an embedded ethics group that is working to anticipate challenging issues and help guide informed consent, prioritize the study of different samples, explore possible regulatory issues pertaining to clinical adoption, and work with international and Indigenous communities to incorporate their genome sequences in these broader efforts.

Many of the individuals whose genomes were sequenced for constructing the new human pangenome reference were originally recruited as part of the 1,000 Genomes Project, a collaborative and international effort funded in part by NIH that aimed to improve the catalog of genomic variants in diverse populations. Because the human pangenome reference is a work in progress, researchers from the international Human Pangenome Reference Consortium continue to add more genome sequences to increasingly improve the quality of the pangenome reference.

Other pangenome papers included in Nature:

Vollger et al. Increased mutation rate and gene conversion within human segmental duplicationsNature. 2023. DOI: 10.1038/s41586-023-05895-y.

Guarracino et al. Recombination between heterologous human acrocentric chromosomesNature. 2023. DOI: 10.1038/s41586-023-05976-y.

Hickey et al. Pangenome graph construction from genome alignment with minigraph-cactusNature Biotechnol. 2023. DOI: 10.1038/s41587-023-01793-w.

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