Pangenome project aims to tell the complete story of human DNA
The mapping of the human genome was a triumph of science, one of the 21st century’s biggest breakthroughs. From the inception of the Human Genome Project in 1990 to the “first draft” published in 2003 to the completion of the first end-to-end genome in 2021, it was a project decades in the making. Like almost all scientific advancements, it wasn’t perfect, and it was really just the beginning.
A major reason for that imperfection is that about two thirds of the human reference genome scientists have been using comes from one person, an American man with European and African ancestry. That tells us a great deal about somewhere between 99 and 99.8% of human DNA. But there’s a lot of diversity in that last 0.2 to 1%, enough to make every single one of us unique. Picking up where the Human Genome Project left off, the Human Pangenome Reference Consortium aims to fill in those gaps. Doing so will reveal to us a great deal about our collective and individual humanity and, the hope is, lead to world-changing medical breakthroughs.
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The HPRC, launched in 2019 by research institutions from the U.S. and Europe, has published a draft human pangenome reference using genomic sequences from 47 people from several parts of the world. The pangenome renders more than 99% of each sequence with high accuracy and reveals over 120 million DNA base pairs not seen before, reports Rockefeller University, one of the institutions involved in the consortium.
“This complex genomic collection represents significantly more accurate human genetic diversity than has ever been captured before,” said Rockefeller’s Erich D. Jarvis. “With a greater breadth and depth of genetic data at their disposal, and greater quality of genome assemblies, researchers can refine their understanding of the link between genes and disease traits and accelerate clinical research.”
Among the operations of the human body that the pangenome could help us better understand is immune responses. That could lead to better organ transplant matches and preventing autoimmune diseases.
In addition to sequencing DNA of people from more parts of the world, HPRC focused on sequencing parent-child trios to get a clearer picture of where individuals get specific genes.
“The differences between mom’s and dad’s chromosomes are bigger than most people realize,” Jarvis said. “Mom may have 20 copies of a gene and dad only two.”
About 90 million of those DNA base pairs that hadn’t been seen before come from chromosomal rearrangement.
“They can have dramatic effects on trait differences, disease, and gene function. With so many new ones identified, there’s going to be a lot of new discoveries that weren’t possible before.”
A major emphasis of the pangenome project is increasing our knowledge of the diversity of human DNA. The HPRC used samples collected by the 1000 Genomes Project. It includes DNA of people from Africa, Asia, the Americas (including the Caribbean), and Europe. Most of the samples used come from Africa, home to the most human diversity.
“In many other large human genome diversity projects, the scientists selected mostly European samples,” Jarvis said. “We made a purposeful effort to do the opposite. We were trying to counteract the biases of the past.”
Often in medicine, traits of people with European ancestry have been used as a baseline, leading to ineffective treatment for people with different backgrounds.
“The most important place in the world to get genomes from is sub-Saharan Africa. It is where we started as a species, and it has the greatest genetic diversity. So, one African American genome is not enough to represent that diversity,” Dr. Ewan Birney of the European Molecular Biology Lab told the BBC.
Still, even with so much diversity in the pangenome, there’s a long way to go. Currently, the samples don’t include DNA from Native American or Aboriginal people.
“It’s still underrepresenting Latin Americans and Indigenous Americans, and … there’s nobody included from Oceania,” University of Maryland human geneticist Timothy O’Connor told Science News. “There’s still a lot more variation that needs to be added to the pangenome to really, truly be representative of everyone.”
In the past, researchers have made unethical use of DNA from certain populations, including making a profit off of unauthorized use of DNA samples. That’s led to mistrust that could hinder the pangenome consortium’s goal of producing genomes from at least 350 people by the middle of next year.
“It’s a complex situation that’s going to require a lot of relationship building,” Jarvis said. “There’s greater sensitivity now.”
He thinks the pangenome consortium is making good progress in that regard, however.
“There are individuals, institutions, and governmental bodies from different countries who are saying, ‘We want to be part of this. We want our population to be represented.’”
That’s a good start, because the more we know about the totality of the human pangenome, the more lives we can save.