New Human Pangenome Reference Released

A new high-quality collection of reference human genome sequences that captures substantially more diversity from different human populations than what was previously available has been published in Nature by a group led by the international Human Pangenome Reference Consortium.   

The new “pangenome” reference includes genome sequences of 47 people, with the researchers keen to increase that number to 350 by mid-2024. With each person carrying a paired set of chromosomes, the current reference actually includes 94 distinct genome sequences, with a goal of reaching 700 distinct genome sequences by the completion of the project. 

The original reference human genome sequence is nearly 20 years old and has been regularly updated as technology advances and researchers fix errors and discover more regions of the human genome. However, it is fundamentally limited in its representation of the diversity of the human species, as it consists of genomes from only about 20 people, and most of the reference sequence is from only one person.  

“Everyone has a unique genome, so using a single reference genome sequence for every person can lead to inequities in genomic analyses,” said Adam Phillippy, a co-author of the main study. “For example, predicting a genetic disease might not work as well for someone whose genome is more different from the reference genome.”  

The current reference human genome sequence has gaps that reflect missing information, especially in areas that were repetitive and hard to read. Recent advances such as long-read DNA sequencing helped researchers fill in those gaps to create the first complete human genome sequence. This complete human genome sequence, released last year as part of the NIH-funded Telomere-to-Telomere (T2T) consortium, is incorporated into the current pangenome reference. 

Using advanced computational techniques to align the various genome sequences, the researchers constructed a new human pangenome reference with each assembly in the pangenome covering more than 99% of the expected sequence with more than 99% accuracy. It also builds upon the previous reference genome sequence, adding over 100 million new bases in DNA. While the previous reference genome sequence was single and linear, the new pangenome represents many different versions of the human genome sequence at the same time. This gives researchers a wider range of options for using the pangenome in analyzing other human genome sequences.   

“By using the pangenome reference, we can more accurately identify larger genomic variants called structural variants,” said Mobin Asri, co-first author of the paper. “We are able to find variants that were not identified using previous methods that depend on linear reference sequences."  Structural variants can involve thousands of bases. Until now, researchers have been unable to identify the majority of structural variants that exist in each human genome using short-read sequencing due to the bias of using a single reference sequence. 

“The human pangenome reference will enable us to represent tens of thousands of novel genomic variants in regions of the genome that were previously inaccessible,” said Wen-Wei Liao, and co-first author of the paper. “With a pangenome reference, we can accelerate clinical research by improving our understanding of the link between genes and disease traits.”