{"doi":"10.1101/2022.03.06.483034","title":"Automated assembly of high-quality diploid human reference genomes","abstract":"The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has greatly benefited society 1, 2 . However, it still has many gaps and errors, and does not represent a biological human genome since it is a blend of multiple individuals 3, 4 . Recently, a high-quality telomere-to-telomere reference genome, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a duplicate genome, and is thus nearly homozygous 5 . To address these limitations, the Human Pangenome Reference Consortium (HPRC) recently formed with the goal of creating a collection of high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity 6 . Here, in our first scientific report, we determined which combination of current genome sequencing and automated assembly approaches yields the most complete, accurate, and cost-effective diploid genome assemblies with minimal manual curation. Approaches that used highly accurate long reads and parent-child data to sort haplotypes during assembly outperformed those that did not. Developing a combination of all the top performing methods, we generated our first high- quality diploid reference assembly, containing only ∼4 gaps (range 0-12) per chromosome, most within + 1% of CHM13’s length. Nearly 1/4th of protein coding genes have synonymous amino acid changes between haplotypes, and centromeric regions showed the highest density of variation. Our findings serve as a foundation for assembling near-complete diploid human genomes at the scale required for constructing a human pangenome reference that captures all genetic variation from single nucleotides to large structural rearrangements.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":11564,"datarank":0.7188645585713289,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.24854042618195632,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.24854042618195632,"corpus_percentile":72.10489672777906,"corpus_rank":3607,"citation_count":22,"citer_count":9,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.9346,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-03-06","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":21287,"name":"Giulio Formenti","orcid":"0000-0002-7554-5991","position":1,"is_corresponding":false},{"id":21320,"name":"Arang Rhie","orcid":"0000-0002-9809-8127","position":2,"is_corresponding":false},{"id":19201,"name":"Andrea Guarracino","orcid":"0000-0001-9744-131X","position":3,"is_corresponding":false},{"id":92287,"name":"Chentao Yang","orcid":"0000-0003-3447-2316","position":4,"is_corresponding":false},{"id":2132,"name":"Jonathan M. 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