Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals¹. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Low-cost whole-genome assembly has enabled the collection of haplotype-resolved pangenomes for numerous organisms. In turn, this technological change is encouraging the development of methods that can precisely address the sequence and variation described in large collections of related genomes. These approaches often use graphical models of the pangenome to support algorithms for sequence alignment, visualization, functional genomics, and association studies. The additional information provided to these methods by the pangenome allows them to achieve superior performance on a variety of bioinformatic tasks, including read alignment, variant calling, and genotyping. Pangenome graphs stand to become a ubiquitous tool in genomics. Although it is unclear whether they will replace linearreference genomes, their ability to harmoniously relate multiple sequence and coordinate systems will make them useful irrespective of which pangenomic models become most common in the future.