Credit: Daniela Velasco/EMBL
It’s been more than 2 decades since the human genome was mapped for the first time. This achievement, while tremendous at the time, was based on the DNA of only a handful of people and left important regions fragmented.
Scientists have worked diligently to improve the human reference genome since then.
In 2022, the first complete sequence of a single human genome filled in many of the remaining gaps. In 2023, the human “pangenome” mapped and stitched together the genomes of 47 individuals in a critical step toward capturing the genetic variation of people around the globe.
The latest datasets, published in 2 back-to-back studies in the journal Nature, present what may be the most complete overview of the human genome to date.
“Our genomes are not static, and neither is our understanding of them,” says Dr Christine Beck from the Jackson Laboratory for Genomic Medicine (JAX) and the University of Connecticut, USA, who co-led the second study.
“For too long, our genetic references have excluded much of the world’s population. This work captures essential variation that helps explain why disease risk isn’t the same for everyone.”
The first paper analysed the genomes of 1,019 people from 5 continents and 28 population groups.
It focused on genomic structural variants – large sections of DNA that have been deleted, duplicated, inserted, inverted or shuffled and which introduce changes to thousands of DNA bases at a time. They contribute to genetic diversity but are also increasingly associated with diseases and cancers.
The most scrambled, repetitive regions are the most difficult to spot and analyse.
The team found and categorised more than 167,000 structural variants, doubling the known amount in the human pangenome.
“We found a treasure trove of hidden genetic variation in these populations, many of which were underrepresented in earlier reference sets,” says co-corresponding author Dr Bernardo Rodríguez-Martín, from the European Molecular Biology Laboratory and Spain’s Universitat Pompeu Fabra and Barcelona Institute of Science and Technology.
“For example, 50.9% of insertions and 14.5% of deletions we found have not been reported in previous variation catalogues. It’s an important step to map blind spots in the human genome and reduce the bias that has long favoured genomes of European descent.”
Rodríguez-Martín says the effort “paves the way for therapies and tests that work just as well for people everywhere”.
The second study took a slightly different approach by sequencing fewer genomes at much greater detail. The researchers used several sequencing technologies to combine highly accurate medium-length DNA reads with longer, lower-accuracy ones.
This strategy allowed them to piece together the near-complete genomes of 65 individuals. They also decoded some of the most difficult to read stretches, including the highly repetitive centromeres, Y chromosomes and an intricate region associated with the immune system’s Major Histocompatibility Complex.
“It’s only been in the last 3 years that finally technology got to the point where we can sequence complete genomes,” says JAX professor Charles Lee, co-senior author of the second paper.
“Now, we’ve captured probably 95% or more of all these structural variants in each genome sequenced and analysed. Having done this for … 65 genomes is an incredible feat.”
Both papers re-sequenced individuals from the 1000 Genomes Project which mapped global genetic diversity in 2015. The new data have been made publicly available.
“We have created a comprehensive and medically relevant resource that can now be used by researchers everywhere to better understand the origins of human genomic variation and see how it is affected by a plethora of different factors,” says Professor Tobias Marschall of Germany’s Heinrich Heine University Düsseldorf, co-senior author on the 2 studies.
“This is a great example of collaborative research opening up new vistas in genomic science and a step towards a more complete human pangenome.”