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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.

There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.

Home ranges have long been studied in animal ecology. Core areas may be used at a greater proportion than the rest of the home range, implying the core contains dependable resources. The Pacific fisher (Pekania pennanti (Erxleben, 1777)) is a rare mesocarnivore occupying a small area in the Sierra Nevada Mountains, California, USA. Once statewide, fishers declined in the 1900s due to trapping, habitat fragmentation, and development. Recently, drought induced by climate change may be affecting this population. We examined space use of fishers in their core versus their home range for levels of anthropogenic modifications (housing density, road density, silvicultural treatments), habitat types, and tree mortality. We found core areas contained more late-successional forest and minimal human activity compared with their territory. Their core had higher levels of dense canopy and higher amounts of conifer cover, while minimizing the amount of buildings, developed habitat, and low canopy cover. Fishers may in effect be seeking refugia by minimizing their exposure to these elements in their core. Conserving landscape components used by fishers in their core areas will be important for the persistence of this isolated population. Key words: anthropogenic, core area, fisher, landscape, Pekania pennanti, refugia. Les domaines vitaux sont étudiés depuis longtemps en écologie animale. Les aires principales pourraient être utilisées en plus grande proportion que le reste du domaine vital, ce qui sous-entend qu'elles renferment des ressources fiables. Le pékan (Pekaniapennanti (Erxleben, 1777)) est un mésocarnivore rare qui occupe une petite région de la chaîne des Sierra Nevada, en Californie (États-Unis). Autrefois présents dans l'ensemble de l'Etat, les pékans ont connu un déclin au 20 (e) siècle causé par le piégeage, la fragmentation de leurs habitats et l'aménagement du territoire. Des sécheresses récentes induites par les changements climatiques pourraient avoir une incidence sur cette population. Nous avons comparé l'utilisation de l'espace par les pékans dans leurs aires principales et dans leurs domaines vitaux pour différents degrés de modifications d'origine humaine (densité de logement, densité de routes, traitements sylvicoles), types d'habitats et taux de mortalité des arbres. Nous avons constaté que les aires principales des pékans renferment plus de forêts en finde succession et très peu d'activités humaines comparativement à l'ensemble de leur territoire. Les aires principales présentent de plus grandes proportions de canopée dense et de plus grandes quantités de couvert de conifères, alors que la quantité de bâtiments, les habitats aménagés et le couvert forestier bas y sont très limités. Les pékans pourraient en fait chercher des refuges en minimisant leur exposition à ces éléments dans leur aire principale. La conservation d'éléments du paysage utilisés par les pékans dans leurs aires principales sera importante pour la persistance de cette population isolée. [Traduit par la Rédaction] Mots-clés: origine humaine, aire principale, pékan, paysage, Pekania pennanti, refuge., Introduction Climate change and anthropogenic modifications to the landscape can directly and indirectly affect wildlife (Wingfield 2008, 2013; Rangel-Negrin et al. 2009). In the Sierra Nevada Mountains of California, USA, [...]

Previous studies suggested that the copy number of the human salivary amylase gene, AMY1 , correlates with starch-rich diets. However, evolutionary analyses are hampered by the absence of accurate, sequence-resolved haplotype variation maps. We identified 30 structurally distinct haplotypes at nucleotide resolution among 98 present-day humans, revealing that the coding sequences of AMY1 copies are evolving under negative selection. Genomic analyses of these haplotypes in archaic hominins and ancient human genomes suggest that a common three-copy haplotype, dating as far back as 800,000 years ago, has seeded rapidly evolving rearrangements through recurrent nonallelic homologous recombination. Additionally, haplotypes with more than three AMY1 copies have significantly increased in frequency among European farmers over the past 4000 years, potentially as an adaptive response to increased starch digestion.

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies where the majority of SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms, we identify 173.2 Mbp of duplicated sequence (47.4 Mbp not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy number when compared to non-African samples. A comparison to a resource of 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs., Competing Interests: COMPETING INTERESTS E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. C.L. is an SAB member of Nabsys and Genome Insight. The other authors declare no competing interests.