The Dawn of Diversity: Release of the New Human Pangenome Reference

The Human Pangenome Reference Consortium has introduced an innovative and diverse reference human genome sequence known as the “pangenome.” Comprising 94 distinct genome sequences, this pangenome aims to expand to 700 sequences by 2024. The release of this comprehensive collection facilitates the identification of larger genomic variants and enhances the accuracy of genomic analysis. By capturing a more extensive range of genome sequences, this new reference offers a more complete and sophisticated representation of human diversity.

Led by the international Human Pangenome Reference Consortium, funded by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health, researchers have released a high-quality collection of reference human genome sequences. This collection surpasses previous versions in capturing a significantly broader spectrum of diversity across various human populations. Initially consisting of genome sequences from 47 individuals, the consortium aims to increase this number to 350 by mid-2024. As each person carries a paired set of chromosomes, the current reference encompasses 94 distinct genome sequences. However, the goal is to reach 700 distinct genome sequences by project completion.

Published in the journal Nature, this work represents one of several papers released by the consortium members. Genome sequences serve as the set of DNA instructions that guide the development and functioning of every living creature. While the genomes of any two individuals are more than 99% identical on average, the remaining small differences contribute to the uniqueness of each person. These genetic variations offer insights into individual health, aiding in disease diagnosis, outcome prediction, and personalized medical treatments.

Using a single reference genome sequence for all individuals can lead to inequities in genomic analyses. Individuals with genomes that differ significantly from the reference genome may experience reduced effectiveness in predicting genetic diseases. To address this issue, scientists create reference human genome sequences as a “standard” for aligning, assembling, and studying other human genome sequences. However, the original reference human genome sequence, nearly two decades old, has limitations in representing the diversity of the human species. It primarily comprises genomes from only about 20 individuals, with most of the reference sequence derived from a single person.

The introduction of the pangenome reference addresses the need for a more inclusive approach. This reference collection encompasses diverse genomes, providing a broader range of options for analyzing other human genome sequences. By utilizing the pangenome reference, researchers can accurately identify larger genomic variants called structural variants. Previous methods relying on linear reference sequences often fail to detect these variants, which can span thousands of bases.

The current reference genome sequence contains gaps that reflect missing information, particularly in repetitive and hard-to-read regions. Recent technological advancements, such as long-read DNA sequencing, have enabled researchers to fill in these gaps and create the first complete human genome sequence. This complete sequence, released last year as part of the NIH-funded Telomere-to-Telomere consortium, is integrated into the current pangenome reference. Leveraging advanced computational techniques, the researchers constructed a new human pangenome reference with each assembly covering over 99% of the expected sequence with more than 99% accuracy. Moreover, they expanded the reference genome sequence by over 100 million bases, incorporating a multitude of different versions of the human genome sequence simultaneously.

The Human Pangenome Reference Consortium’s endeavor to enhance the pangenome reference comes at a projected cost of $40 million over five years. This funding supports various aspects, including creating the reference, improving DNA sequencing technology, operating a coordinating center, conducting outreach, and developing resources for the research community. Many individuals whose genomes were sequenced for constructing the pangenome reference were originally recruited as part of the 1,000 Genomes Project, a collaborative international effort aimed at enriching the catalog of genomic

Related links:

• Nature Article: A draft human pangenome reference
• Nature Article: Increased mutation rate and gene conversion within human segmental duplications
• Nature Article: Recombination between heterologous human acrocentric chromosomes
• Nature Biotechnology Article: Pangenome graph construction from genome alignment with minigraph-cactus