{"doi":"10.1093/bioinformatics/btac186","title":"TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity","abstract":"MOTIVATION: Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and reconstructing the phylogeny of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains exemplify these difficulties since there are only hundreds of phylogenetically informative sites but millions of genomes. For such datasets, we set out to develop a method for building the phylogenetic tree of genomic haplotypes consisting of positions harboring common variants to improve the signal-to-noise ratio for more accurate and fast phylogenetic inference of resolvable phylogenetic features. RESULTS: We present the TopHap approach that determines spatiotemporally common haplotypes of common variants and builds their phylogeny at a fraction of the computational time of traditional methods. We develop a bootstrap strategy that resamples genomes spatiotemporally to assess topological robustness. The application of TopHap to build a phylogeny of 68 057 SARS-CoV-2 genomes (68KG) from the first year of the pandemic produced an evolutionary tree of major SARS-CoV-2 haplotypes. This phylogeny is concordant with the mutation tree inferred using the co-occurrence pattern of mutations and recovers key phylogenetic relationships from more traditional analyses. We also evaluated alternative roots of the SARS-CoV-2 phylogeny and found that the earliest sampled genomes in 2019 likely evolved by four mutations of the most recent common ancestor of all SARS-CoV-2 genomes. An application of TopHap to more than 1 million SARS-CoV-2 genomes reconstructed the most comprehensive evolutionary relationships of major variants, which confirmed the 68KG phylogeny and provided evolutionary origins of major and recent variants of concern. AVAILABILITY AND IMPLEMENTATION: TopHap is available at https://github.com/SayakaMiura/TopHap. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.","journal":"Bioinformatics","year":2022,"id":264956,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.912,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":377103,"name":"Sayaka Miura","orcid":"0000-0001-9881-2848","position":1,"is_corresponding":false},{"id":98158,"name":"Maxwell Sanderford","orcid":"0000-0002-8173-9952","position":2,"is_corresponding":false},{"id":819399,"name":"Tenzin Dolker","orcid":null,"position":3,"is_corresponding":false},{"id":381445,"name":"Qiqing Tao","orcid":"0000-0001-7360-409X","position":4,"is_corresponding":false},{"id":309145,"name":"Steven Weaver","orcid":"0000-0002-6931-7191","position":5,"is_corresponding":false},{"id":69662,"name":"Sergei L. Kosakovsky Pond","orcid":"0000-0003-4817-4029","position":6,"is_corresponding":false},{"id":3959,"name":"Sudhir Kumar","orcid":"0000-0002-9918-8212","position":7,"is_corresponding":false},{"id":554081,"name":"Marcos A. Caraballo‐Ortiz","orcid":"0000-0003-4063-3657","position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":null,"created_at":"2026-07-19T00:26:45.905331Z","pmid":"35561179","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}