Scientists release human “pangenome” reference

The first human genome sequence, generated by the Human Genome Project 20 years ago, has served as a reference for researchers to use in their genomics studies. This first human genome reference sequence did not represent a single person; rather, it was assembled with genomic data from about 20 people to be a general-purpose tool, against which scientists could compare other human genome sequences.

Over the years, researchers have regularly improved that reference sequence, fixing errors and adding missing pieces. Recently, new genome sequencing technologies, particularly long-read DNA sequencing methods, have made it possible to read longer stretches of DNA at once. These technologies allowed researchers from the NIH-funded Telomere-to-Telomere (T2T) Consortium to fill in the missing gaps and create the first complete human genome sequence in March of last year. While the original human genome reference sequence has been regularly improved, it still consisted of genomes from only around 20 people, which does not adequately represent the diversity of our species.

On average, any two individuals' genomes are more than 99% identical, but that still leaves millions of differences. A more inclusive human genome reference sequence will allow researchers and clinicians to identify and understand the small genomic differences that make each person unique, providing genomic insights that could be relevant for health and disease management.

Last month, the NHGRI-funded Human Pangenome Reference Consortium released a high-quality collection of human genome reference sequences, which together comprise a human "pangenome" reference. Encompassing genome sequences from 47 people of diverse ancestries, the human pangenome reference captures significantly more population diversity than the previous reference sequence. Specifically, a set of individuals previously studied in the 1,000 Genomes Project had their genomes sequenced with very high accuracy.

The current human pangenome reference consists of genome sequences from 47 people of different ancestral backgrounds, including people from Africa, Asia, the Americas, and Europe. Scientists in the consortium aim to increase the number of represented genomes to 350 by mid-2024, when the project is expected to be completed. The new human pangenome reference adds 119 million bases to the existing human genome reference sequence. This will allow researchers to identify new genomic variants that were not previously detectable and will better represent human diversity

The main human pangenome reference paper is one of several papers published in Nature that report findings generated with the new human pangenome reference. This included developing a map of single-nucleotide variants within segmental duplications and observing patterns of recombination between different parts of chromosomes.

As a truly collaborative effort, the Human Pangenome Reference Consortium consists of researchers from various institutions around the world working to create a more complete and sophisticated collection of reference genome sequences. As the construction of a human pangenome reference is still ongoing, researchers from the consortium are working hard to add more genome sequences and improve its quality and diversity.

Importantly, the Human Pangenome Reference Consortium has an embedded ethical, legal, and social implications (ELSI) research group to guide informed consent, sample prioritization, regulatory policies, and collaborations with international and Indigenous communities. This group ensures that the collection and use of the genomic data are ethical and that communities around the world are engaged with the research process.

Generating the human pangenome reference is part of NHGRI's ongoing effort to account for global diversity in genomics research, which is important for advancing and implementing genomic medicine in an equitable way.

Read the main paper here and the NHGRI press release here. Find more resources about the human pangenome reference, including videos, multimedia, and news coverage, on the genome.gov website.

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