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The joke about the Human Genome Project is how many times it’s been finished, but not actually.

The first time was in 2000,  when Bill Clinton announced the “first survey of the entire human genome” at a White House ceremony, calling it “the most important and most wondrous map ever produced by humankind.”

But the job wasn’t done. A year later, the triumph was announced again, this time with the formal publication of a “draft” of “the genetic blueprint for a human being.” In 2003, researchers had another go at the finish line, claiming the “successful completion” of the project, citing better levels of accuracy. Nineteen years later, in 2022, they again claimed victory, this time for a really, truly “complete” sequence of one genome—end to end, no gaps at all. Pinkie promise.

Today, researchers announced yet another version of the human genome map, which they say combines the complete DNA of 47 diverse individuals—Africans, Native Americans, and Asians, among other groups—into one giant genetic atlas that they say better captures the surprising genetic diversity of our species.

The new map, called a “pangenome,” has been a decade in the making, and researchers say it will only get bigger, creating an expanding view of the genome as they add DNA from another 300 people from around the globe. It was published in the journal Nature today.

“We now understand that having one map of a single human genome cannot adequately represent all of humanity,” says Karen Miga, a professor at the University of California, Santa Cruz, and a participant in the new project.

People’s genomes are largely alike, but it’s the hundreds of thousands of differences, often just single DNA letters, that explain why each of us is unique. The new pangenome, researchers say, should make it possible to observe this diversity in more detail than ever before, highlighting so-called evolutionary hot spots as well as thousands of surprisingly large differences, like deleted, inverted, or duplicated genes, that aren’t observable in conventional studies.

The pangenome relies on a mathematical concept called a graph, which you can imagine as a massive version of connect-the-dots. Each dot is a segment of DNA. To draw a particular person’s genome, you start connecting the numbered dots. Each person’s DNA can take a slightly different path, skipping some numbers and adding others.

One payoff of the new pangenome could be better ways to diagnose rare diseases, although practical applications aren’t easy to name. Instead, scientists say it’s mainly giving them insight into some of the “dark matter” of the genome that’s previously been hard to see, including strange regions of chromosomes that seem to share and exchange genes.

For now, most biologists and doctors will stick to the existing “reference genome,” the one first produced in draft form in 2001 and gradually improved. It answers most questions researchers are interested in, and all their computer tools work with it.

The reason a reference genome is important is that when a new person’s genome is sequenced, that sequence is projected onto the reference in order to organize and read the new data. Yet since the current reference is just one possible genome, missing bits that some people have, some information can’t be analyzed and is usually ignored.

Researchers call this effect “reference bias” or, more simply, the streetlamp problem. You don’t see where you don’t look.

“It’s hard to appreciate just how important the current reference is. We use it like a coordinate system or a map, and we refer to it constantly when we talk about genes,” says Benedict Paten, a computational biologist, also at Santa Cruz, and the senior author of the report.. “But it’s both incomplete and lacks diversity. It lacks the things that make us different—in other words, the interesting bits.”

Officials with NIH said they hoped the new update to the genome map would make gene research more “equitable.” That’s because the more different your genome is from the current reference, the more information about you could be missed. The existing reference is largely the DNA of one African-American man, although it includes segments from several other people as well.

“If the genome you want to analyze has sequences that are not in that reference, they will be missed in the analysis,” says Deanna Church, a consultant with the business incubator General Inception, who previously held a key role at NIH managing the reference genome. “In reality, the notion that there is a ‘human genome’ is really the problem,” she says. “The current version is the simplest model you can make. It made sense when we started … But now we need better models.”  

The pangenome, which itself remains at draft stage, was constructed with the help of two newer technologies. One is a type of sequencing machine that reads out very long stretches of DNA in one go. Most sequencing is done by shredding DNA into tiny bits, under 200 letters long. But the new machines, made by the company Pacific Biosciences, produce continuous readouts of 10,000 letters at once.

Such “long reads,” as researchers call them, are like extra-large puzzle pieces that are much easier to arrange correctly in the actual order they’re present in a person’s genome. 

That puzzling-together process—called genome assembly—is the other area where researchers say they’ve made advances with new computation tools. Even so, organizing and comparing 47 genomes at once (each with about 6 billion pairs of DNA letters) remains a gnarly problem.

“There is a huge amount of really interesting computer science that has been published in not-so-glamorous journals,” says Paten, who has been working on the pangenome for more than 10 years.  

Paten also admits that no one other than specialists will want to look at their data visualization tools, which display the alternate arrangements of DNA as complicated loops and knots called “spaghetti diagrams.” Instead, real success will come if the pangenome can fade into the background and become the new plumbing of the genetic age, something researchers can use without ever seeing.

Experts think it’s too soon to say whether that will happen. “I hope it will, but it will be a tough road,” Church says. “So much of our tooling and infrastructure is based on having a linear representation that getting people to change their mindset will be hard.” 

One thing is for sure, says Erik Garrison, a computational biologist at the University of Tennessee and also among the leaders of the project. The human genome isn’t finished and never will be.

“Once you start talking about a pangenome, it’s always going to be incomplete, and it’s never going to end. Every individual is going to have a different genome, so it’s an infinite process,” says Garrison. “Every population and every generation could have its own pangenome.”