The Human Genome: Global DNA data gets diversity bump

When an international group of scientists in the Human Genome Project (HGP) published the very first sequence of the human genome in 2003, it consisted of three billion units of DNA. It was hailed as a blueprint of human life.

Genome mapping, as it is known, promised many things and it delivered, perhaps most notably in evolutionary biology — the science of how life has evolved on Earth.

But, despite its being a monumental scientific achievement, it’s had its limitations. In short, the data lacked diversity.

Most of the data for the original reference genome stemmed from only one person, although it included some additional data from about 20 other people. A reference genome is a standard representation of the human genome sequence that researchers use to compare DNA sequences that they generate in their studies, for example when they are looking for treatments for diseases.

A more diverse approach: The human pangenome reference

Now, scientists at the University of Washington School of Medicine (UW Medicine) say they have created a new reference genome that will improve the diversity and equity in the Human Genome Project.  

Known as the human pangenome reference, they say it contains nearly full genomic data from 47 people whose ancestry traces back to different populations around the globe.

"The pangenome approach represents a new way of thinking about human genetic variation," said Evan Eichler, professor of genome sciences at UW Medicine in Seattle and one of the senior scientists in the Human Pangenome Reference Consortium, ahead of the publication of their study in the journal Nature.

The medical genetics revolution

Genomic medicine has been at the heart of the biological revolution. By sequencing the genomes of more than a million people since 2003, scientists have seen how genetic variation between people affects the risk of disease.

"The idea that you can get the whole genome sequence of a sick baby and understand why they're sick within days is remarkable," said David Curtis, a professor of medical genetics at University College London, UK.

For Curtis, it's this routine use of genetic technology in clinical practice that is the biggest benefit to come from the HGP.

"In the last few years of big sequencing studies, we've found the first gene for schizophrenia. Now we have 10. If these genes are damaged, it has a huge effect on your schizophrenia risk," Curtis told DW.

And it's not just schizophrenia where we've linked genes with diseases. Scientists have found mutated genes that cause cancers, heart disease, diabetes, you name it. The next big benefit lies in being able to create new therapies by studying the genetic mutations in the lab.

We've already seen some success in gene-based therapies, from retraining immune cells to fight cancer to using CRISPR-Cas9 gene editing tools to treat sickle cell disease.

"Genetics is very helpful to study diseases and there's massive scope for genetic therapies," said Curtis.

The limits of medical genetics

But the new boom has also shown the limits of genetic medicine. The fact remains that genes are just one factor in disease outcome, and few inherited diseases are caused by mutation in a single gene.

In the case of schizophrenia, Curtis said, only about 1% of people with the disease have a mutation in one of those 10 identified genes. In total, there are more than 250 genetic "risk factors" for schizophrenia. The sheer number of risk factors, plus the fact we don't understand how these contribute to the disease, create a real challenge for medicine.

"Some people have a mutation and they haven't got schizophrenia, or they've got a different disease entirely. The whole relationship between genetic mutation and disease has gotten shakier [since genome sequencing]," said Curtis.

Grandad was a neanderthal, and other human evolutionary tales

Where genome sequencing has been truly groundbreaking is in evolutionary biology.

"We can compare the human genome sequence to those of our close relatives and place our species within that broader evolutionary context. It's shown us that human history was much more dynamic than anyone could have predicted," Anders Bergstrom, an evolutionary biologist at the University of East Anglia, UK, told DW.

Scientists studying the genome sequences of early and modern humans have shown that our ancestors interbred with other hominins like Neanderthals and Denisovans. We now have insights into the lives of  Neanderthal communities in central Europe, providing clues about their population decline, as well as tracing the genetic heritage of long-lost people like the Minoans in modern-day Cretans.

By studying ancient DNA and the little traces of ancestors inside of us, we're understanding how our species has expanded across the world, brought cultural advances like farming to distant lands, and developed resistances to diseases along the way.

What is a human?

The biggest questions about genetics have yet to be answered. For one, only about 1% of the genome codes proteins — we don't really understand what much of the other 99% does.

For Bergstrom, the biggest question genetics can answer is what makes us human.

"Almost all of the progress that has been made in genetics in the last 20 years is about explaining differences among humans, but it doesn't tell us about what's universal among us," he said.

Genome sequencing has changed how we view ourselves, but mostly by giving scientific backing for the idea of individualism. The thinking goes that everyone's genetic code is different (even identical twins don't have exactly the same code), so by identifying all the tiny genetic variations between people, we can see what makes each of us different.

This is often productive. Genome sequencing has shown, for example, that "race" is a social construct not rooted in genetics (there is more genetic variation within racial groupings than between them). But by always looking for differences, we lose track of what makes us collectively humans rather than 8 billion individual ape-like beings on the same planet.

Take chimpanzees. We know we have 96% genetic similarity to them, but we don't really understand how the 4% difference makes us more "human" than our lice-grooming cousins.

"It's a fundamental question," said Bergstrom. "What is it that makes us humans and unique as a species?"

Increasing genome diversity

The progress made in the last twenty years was not without its failings. More than a million genomes have been sequenced so far, but 95.2% of the data in genetics studies comes from European genomes.

"It didn't represent diversity among humans at all. If our science is biased towards people of a particular type of ancestry, then we won't be able to offer the same quality of personalized medicine to different people," said Bergstrom.

Things are changing. The Nigerian 100k Genome Project aims to sequence, well, 100,000 genomes in Nigeria. Similar efforts are underway elsewhere in Africa, and Asia and South America. The hope is that more routine and cheaper genome sequencing technologies around the world will benefit all of humanity.

Edited by: Carla Bleiker

This article was originally published on April 13, 2023. It was last updated on May 10, 2023, to include information on the human pangenome reference, published in the journal Nature.