More than 20 years after scientists first released the draft human genome sequence, the book of life has been long overdue for its rewriting.
A more accurate and inclusive edition of our genetic code was published on Wednesday, marking a major step towards a deeper understanding of human biology and personalized medicine for people of different racial and ethnic backgrounds.
Unlike previous references — which were based largely on the DNA of a mixed-race male from Buffalo, with input from several dozen other individuals, mostly of European descent — the new “pangenom” combined the nearly complete genetic sequences of 47 males and females. women of various origins, including African Americans, Caribbean Islands, East Asia, West Africa, and South America.
Updated genome maps are an important tool for scientists and clinicians who hope to identify genetic variations associated with disease. It also holds promise for providing treatments that could benefit everyone, regardless of their race, ethnicity or ancestry, the researchers said.
“It's been needed for a long time – and they've done an excellent job,” said Ewan Birney, a geneticist and deputy director general of the European Laboratory for Molecular Biology, who was not involved in the effort. “This will increase our understanding of variation, and then that research will open up new opportunities towards clinical applications.”
Powered by the latest DNA sequencing technology, the pangenome assembles 47 unique genomes into a single resource, providing the most detailed picture of the code that drives our cells. The gaps in the previous references are now filled, with nearly 120 million previously missing DNA letters added to the three billion letter long code.
Gone is the notion of totemic strands of DNA extending six feet when unfolded and stretched in a straight line. Now, the rebooted reference resembles a corn maze, with alternate pathways and sideways that allow scientists to explore the wider genetic diversity found in humans around the world.
Dr. Eric Green, director of the National Human Genome Research Institute, the government agency that funded the work, likened the pangenome to a new kind of bodywork manual for the automotive repair shop. If previously each mechanic only had design specifications for one type of car, now there is a master plan that covers different makes and models.
“We've gone from having one very good blueprint of Chevy to now having blueprints of 47 representative cars from each of 47 different manufacturers,” he said.
Knowing what to do with Kelley Blue Book genomics is going to involve a steep learning curve. New analysis tools are needed. The coordinate system had to be redefined. Widespread adoption will take time.
“Making this easy for the public to use is a lot of work,” said Heidi Rehm, chief genomics officer at Massachusetts General Hospital in Boston, who was not involved with the project.
But in time, experts say, the pangenome will revolutionize the field of genomic medicine.
“We would benefit from understanding ourselves as a species much better,” said Evan Eichler, a genome scientist at the University of Washington. Dr. Eichler is among more than 100 scientists and bioethicists who describes the new pangenome reference in the journal Nature.
Project architects are continuing to add more population groups, with the goal of including at least 350 high-quality genomes covering the majority of global human diversity.
“We want to represent all branches of the human tree,” said Ira Hall, a geneticist who directs the Yale Center for Genomic Health.
Some of the new genomes will come from New Yorkers who previously participated in research programs at the Mount Sinai Health System. If their initial DNA data appears to reflect a particular, underrepresented genetic background, the individual will be invited to participate in the pangenome project.
However, some gaps may never be included in publicly available references – by design.
Previous attempts to capture human genetic diversity often extracted sequence data from marginalized populations without regard to their needs and preferences. Informed by this ethical misstep, the pangenome coordinators are now collaborating with Indigenous groups to develop formal policies around data ownership.
“We are still grappling with issues of indigenous and tribal sovereignty,” said Barbara Koenig, a bioethicist at the University of California, San Francisco, who was involved in the project.
In Australia, researchers are combining DNA sequences from various Aboriginal peoples into a similar repository that will be merged with open source pangenomes, but then stored behind a firewall. According to Hardip Patel of Australia's National Center for Indigenous Genomics in Canberra, the scientists next plan to consult with community leaders about whether or how to make the data accessible via request.
Some Indigenous advocates would like to see the pangenome project go further. Keolu Fox, a genomic scientist at the University of California, San Diego, who is a native Hawaiian has suggested training the next generation of Indigenous scientists to have greater agency over genomic data.
“It is finally time for us to decentralize power and control and redistribute it among the communities themselves,” said Dr. Fox.