The Human Pangenome Project: a global resource to map genomic diversity

Abstract

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.

Figure 1:. The Human Pangenome Reference Consortium.

This diagram provides an overview of the HPRC’s several components. Collect: I,000 Genomes samples jump-start the project and will be followed by additional samples collected through community engagement and recruitment. Sample selection efforts will ensure the graph-based reference captures global human genomic diversity. Sequence: Long-read and long-range technologies are used to generate genome graphs and bridge gaps in difficult-to-assemble genomic regions. Assemble: Telomere-to-telomere finished diploid genomes will foster variant discovery, especially in complex, difficult to assemble genomic regions. Construct: Scalable bioinformatics approaches assemble, QC, call variants, and benchmark graph assembly accuracy. The graph is annotated with gene descriptions and transcriptome data, making it more accessible and interpretable. Utilize: Collaboration across scientific and stakeholder communities will create a new ecosystem of analysis tools. Clinical applications and research use will involve analysis, validation, interpretation, and publication of results. Outreach: Members of the HPRC Outreach community engage and educate the user community and broadly share all genomic products and informatics platforms. ELSI: ELSI scholars will develop selection processes and policy frameworks that meet investigator needs while respecting research partner autonomy and cultural norms.

Figure 2:. Standards were developed through a pilot benchmark study of one individual.

Multiple long-read and long-range technologies and computational methods were evaluated to develop the combination of platforms and an automated pipeline that provides the most complete and accurate genome graph.

Figure 3:. The Human Pangenome Reference.

Graph-aware mappers can be used to genotype samples by directly mapping against the graph. This simplified example shows how to create a pangenome graph for four people and calculate the allele frequency of three variants. Iterating through each individual produces the graph structure, which improves as new genomes are added. Genomic data is arranged into a sequence variation map based on edges. Alternative haplotypes are depicted as alternate pathways across the graph, with the edges being the primary data-bearing elements. The pangenome reference catalogs genomic variation and allows for population- scale analysis thanks to its graph structure. Tracing a path through the network and connecting sequences at access edges yields haplotypes for individuals. For clinical interpretation, allele frequencies are reported.