“The” human genome was always a mistake

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The a person The genome project, which published its results 20 years ago last month, is a landmark in biology. It was also called something fake. After all, there is no such thing as “the” human genome. Instead, there are 8bn individuals, each of whom shares most of DNA– but that’s not all. The genome published by the Human Genome Project in 2003 was assembled from twelve anonymous blood donors in and around Buffalo, New York state.

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But there is more to life than Buffalo. That, in fact, is the reason behind this week’s publication, in Nature, of a set of 47 new “reference” genomes taken from individuals on four continents (Africa, both the Americas, and Asia). The idea of ​​the Human Pangenome Project, the group behind the publications, is that rather than relying on one “reference” genome, it would be better to have several, and between them ensure that they capture so much genetic diversity Homo sapiens as possible.

Compared to the total size of the genome, the amount of diversity in question is small. Two people chosen at random will share about 99.6% of theirs DNA. That similarity is why the original genome produced by the Human Genome Project has been so useful. The annotated sequences of genetic code are the baseline. Other genomes can be compared to it to look for variants, whether harmful or beneficial.

But although people are generally the same, their differences are important. A relatively recent mutation, for example, means that adults with ancestry from northern Europe, or parts of India and the Middle East, are more likely to be lactose intolerant ( sugar found in milk) to digest than those from other places. What variation deserves to be treated as the standard?

Sometimes, the limits of use of a single reference have direct medical implications. A set of genes called hla, for example, involved in running the immune system. They are highly variable, and mutations in them have been associated with autoimmune diseases such as type-1 diabetes. One study, published in 2015, found that because many next-generation sequencing technologies are not completely accurate, comparing reads from the region with the same reference genome resulted in errors about 20% of the time. Another paper, published in 2022, found that relying on the reference genome meant that details of some gene changes found in people with African ancestry were missing, and apparently co -related to cancer, poorly understood.

In the age of home gene testing kits, powered by falling sequencing costs (see chart), 47 genomes may not be that impressive. But the existing sequencing technologies give incomplete results. They are responsible for reading short excerpts of DNA, and does not deal well with the long, repetitive regions that line the genome. As Evan Eichler, a geneticist at the University of Washington, said at a press conference: “There are complex forms of [genetic] change where we know the existing technology isn’t doing a good job… it misses about two-thirds of those.” The Pangenome Project uses newer and more accurate methods. That allows researchers to see variations that might otherwise be missed, and to better understand how, exactly, mutations arise.

The new genomes, then, represent a major improvement on the status quo. But there are still gaps. All the genomes were drawn from material donated to the 1,000 Genomes Project, a collection of anonymous samples that began in 2008. It suffers from a lack of donations from the Pacific islands and the Middle East. The researchers intend to fix that. But increasing diversity is unlikely to mean sampling every corner of the world equally. The majority of human genetic diversity is found within Africa, the species’ homeland. (People in the rest of the world are descended from a small band that migrated out between 50,000 and 70,000 years ago.)

The researchers do not intend to catalog every genetic variation that exists. It would be a Sisyphean task: as Tobias Marschall, a computational geneticist at Heinrich Heine University, said, every baby is born with dozens of mutations that none of its parents have. Benedict Paten, a geneticist at the University of California, Santa Cruz, and one of the authors of this week’s collection of papers, says the goal is instead to reach 350 high-quality genomes. That should allow researchers to capture most of the genetic variation thought to be out there. That gives humanity a much more representative picture of one of its favorite research subjects – itself.

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