Do you already know him? “It’s been completed many times before, but never really conclusively.” This is a joke that is often quoted in professional circles about the human genome project. US President Bill Clinton first announced the “first survey of the entire human genome” at a White House ceremony in 2000, calling it “the most important and wondrous map ever created by mankind”.
But the work wasn’t quite done yet. A year later, triumph was again proclaimed, this time with the official release of a “blueprint” of “the genetic blueprint for a human.” In 2003, researchers took another shot and announced the “successful completion” of the project, citing a higher level of accuracy. Nineteen years later, they announced victory again in 2022, this time for a truly complete sequence of a genome, from start to finish, without any gaps. Big word of honour.
Recently, scientists led by the computer biologist Benedict Paten from the University of California at Santa Cruz (UCSC) presented another version of the human genome in the journal Nature, in which they analyzed the complete DNA of 47 different individuals – including Africans, Native Americans and Asians in a vast genetic atlas designed to better reflect the surprising genetic diversity of our species. That is why the new DNA map is also called the pangenome (the prefix “pan” means something like “whole” or “with all those involved”).
It took ten years to create them. Matching the joke, it’s not finished yet either. According to the researchers involved, it will continue to grow by adding the DNA of another 300 people from around the world to create an even more comprehensive picture of the genome. “We now understand that a map of a single human genome cannot adequately represent all of humanity,” says Karen Miga, a UCSC colleague of Paten.
Genomes: diversity in detail
Basically, the genomes of different people are largely similar. However, there are hundreds of thousands of small differences, sometimes as little as a single letter of DNA (a base), that make us all unique. The new pangenome aims to observe this diversity in more detail than ever before and help identify so-called evolutionary hotspots and thousands of surprisingly large differences: for example, deleted, base-sequence-reversed and duplicated genes that cannot be observed in conventional studies.
The pangenome is based on a mathematical concept, a graph that can be thought of as a giant version of the connect the dots game. Each dot is a section of DNA. To draw the genome of a specific person, you start connecting the numbered dots. In doing so, each person’s DNA can take a slightly different route, skipping some numbers and adding others.
The practical applications of the new pangenome are not easy to name. One advantage could be that rare diseases can be better diagnosed. In addition, the scientists hope that it can provide them with insights into the “dark matter” of the genome, which was previously difficult to find. These include, for example, strange chromosome regions that share and exchange sections of DNA with one another.
For now, most biologists and physicians will stick to the existing reference genome, first drafted in 2001 and gradually improved. It answers most of the questions researchers are interested in and all their computing tools work with it.
“Fairer” genetic research through genome maps?
A reference genome is still important because when a new person’s genome is sequenced, that sequence is projected onto the reference genome to help organize and decipher the new data. However, since the current reference genome is only one possible genome, missing parts that other people possess, some information cannot be analyzed and is usually ignored. Researchers call this effect “reference distortion” or, more simply, the streetlight problem. If you don’t look, you won’t see anything.
“It’s hard to appreciate the importance of the current reference. We use it like a coordinate system or a map, and we refer to it all the time when we talk about genes,” says Paten. “But it’s both incomplete and not diverse enough. It’s missing the things that make us different – in other words, the interesting parts.”
Officials at the National Institutes of Health (NIH) hope the new update to the genome map will make genetic research “fairer.” Because the more our genome differs from the current reference, the more information about us could be lost. The existing reference map consists largely of DNA from an African American male, although it also contains segments from several other people.
“If the genome you want to analyze contains sequences that aren’t in the reference, the analysis will miss them,” says Deanna Church, a consultant at General Inception’s incubator, who formerly played a key role at the NIH in managing the reference genome held. “In reality, the idea that there is a ‘human genome’ is the real 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.”
Putting together the puzzle of humanity
The pangenome, which is still in the draft stage, was created using two new technologies. On the one hand, a sequencing machine that can read very long sections of DNA in one go helped. In most sequencing methods, DNA is chopped into tiny pieces of less than 200 letters. The new devices from Pacific Biosciences, on the other hand, can read 10,000 letters at once. Such “long reads,” as the researchers call them, are like extra-large jigsaw pieces that are much easier to arrange in the right order in a person’s genome.
This jigsaw puzzle-making process, called genome assembly, is the other area where the researchers say they’ve made progress using new computational tools. Still, organizing and comparing 47 genomes at once (each containing about six billion pairs of DNA letters) remains a tricky problem.
“There’s a huge amount of really interesting computer science that’s been published in not-so-glamorous journals,” says Paten, who worked on the pangenome for more than a decade.
Paten also acknowledges that no one but professionals wants to look at their data visualization tools, which depict the alternate arrangements of DNA as intricate loops and knots called “spaghetti diagrams.” Real success will come only when the pangenome takes a back seat and becomes the new genetic-age plumbing system that researchers can use without ever seeing.
Pangenom: “It’s a never-ending process”
According to experts, it is still too early to tell whether this will work. “I hope so, but it’s going to be a tough road,” says Church. “So much of our tools and infrastructure is based on a linear representation that it’s going to be difficult to get people to change their minds.”
One thing is for sure, says Erik Garrison, a computational biologist at the University of Tennessee and also one of the project’s leaders. The human genome is not finished and never will be.
“Once you start talking about a pangenome, it will always be incomplete, and it will never end. Every individual will have a different genome, so it’s a never-ending process,” says Garrison. “Each population and generation could have its own pangenome.
(jl)