The pan-genome aims to better reflect the diversity of human populations
Darryl Reja, NHGRI
Efforts to expand the Human Genome Project by capturing the diversity of people around the world have produced the first draft of a new resource called the ‘Pan Genome Reference’.
What is Pan Genome?
This is a set of genomes from many individuals that have been put together to indicate where the sequences are identical or different. The draft human pan genome consists of 47 genomes, with plans to expand this to 350 genomes by 2024.
why do you need it?
The pan-genome helps researchers discover the effects of genetic variants and develop treatments for conditions associated with those variants. Some variants are now essentially invisible to researchers because they rely on a single reference genome.
Wait a minute, what is a reference genome?
A type of map. When researchers sequence someone’s DNA, they combine a number of fragments based on where they fit in the reference her genome. It’s like looking at an anatomy textbook and figuring out where each bone fits to put together a skeleton. It works fine for most bones, but some people have extra bones that aren’t in the textbook, such as cervical ribs. There’s always been a good chunk,” says Evan Eichler of the University of Washington in Seattle.
Whose DNA was the reference genome based on?
The reference genome was supposed to be made from a mixture of DNA from 20 anonymous donors, but in the end 73% of it came from one individual. Subsequent analysis showed that person was African-American, and the next largest donor was about 6%, predominantly East Asian.
We have already sequenced millions of genomes. Why haven’t we got the Pan Genome yet?
Many genomes we have sequenced are far from complete. In fact, when the Human Genome Project was declared “complete,” the single reference genome was only 92% complete. At the time, only short pieces of DNA could be sequenced. Many of these small fragments could not be reconstructed because much of the genome is highly repetitive. The Pan-Genome Project uses a method of generating longer fragments known as ‘reads’. As a result, the pan-genome is based on very high-quality sequences that are 99% complete.
Whose genome is included in the pan-genome?
I don’t know, says Karen Miga of the University of California, Santa Cruz. Anonymous donors were participants in a previous initiative called the 1000 Genomes Project, and were selected based on how well genomes collectively reflect human diversity. About half of the donors are African or of African ancestry, but more are needed, Eichler says. “Africans are so diverse, and all humans descended from African populations, that Africa needs to be sampled deeper before we can have a true human pan-genome reference,” he says. .
How much human variation does the pangenome capture?
Because mutations originated in distant ancestors with many descendants, they contain many common variants shared by many people. I need a pan-genome that contains the whole genome, but that’s not critical. “What we want to achieve is to be able to analyze all the variations right now, the reads are unmapped,” says Tobias Marschall of the Heinrich Heine University Düsseldorf, Germany. “Now every fragment of the genome has a destination.”
Will biologists use pan-genome referencing instead of single-reference genomes?
Some will. But Jesse Gillis of the University of Toronto, Canada, who compiled another “consensus reference” in 2021, says it will take a very long time to switch to using mostly pan-genomes. Researchers have developed many methods and software based on a single reference, but the pan-genome is more complex, he says.Pan-genome, a member of his team, Benedict of the University of California, Santa Cruz. Patten admits that people won’t switch if the costs outweigh the benefits. But the PanGenome team has developed a software tool that’s just as fast, he says.
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