{"doi":"10.1101/2025.10.20.683446","title":"Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans","abstract":"<h4>Summary: </h4> Humans exhibit significant phenotypic differences from other great apes, yet pinpointing the underlying genetic changes has been limited by incomplete reference genomes and a reliance on single assemblies to represent a species. We aligned 20 telomere-to-telomere (T2T) assemblies spanning great ape divergence and variation to define 1,596 Consensus HAQERs (consensus human ancestor quickly evolved regions), regions that diverged rapidly between the human-chimpanzee ancestor and an ancestral node of modern humans. Unlike prior HAQER sets, Consensus HAQERs incorporate population variation, reducing the likelihood of intraspecies variation appearing as interspecies divergence. Consensus HAQERs exhibit signatures of elevated mutation rates, ancient positive selection, bivalent regulatory function, are enriched in disease-linked loci, and often emerged in previously inaccessible repetitive DNA. Through multiplex, single-cell enhancer assays, we identify HAQERs as active enhancers in the developing brain and cardiomyocytes, highlighting their potential contributions to human-specific gene regulation across multiple tissues. <h4>Highlights</h4>  ● Telomere-to-telomere alignments of diverse human and great ape genomes identify 1,596 Consensus HAQERs, regions of rapid sequence divergence separating human ancestors from other great apes. ● Consensus HAQERs exhibit signatures of both elevated mutation rates and ancient positive selection. ● HAQERs are enriched in bivalent regulatory elements and disease-linked loci. ● Multiplex, single-cell gene regulatory assays identify HAQERs as enhancers in the developing heart and brain.","journal":null,"year":2025,"id":10088,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":37.91700569568755,"corpus_rank":716,"citation_count":3,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6562,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-10-21","fair_score":38.3333,"fair_percentile":19.217238346525946,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":51325,"name":"Riley J. Mangan","orcid":"0000-0003-3342-3934","position":1,"is_corresponding":false},{"id":85739,"name":"Seth Weaver","orcid":"0000-0002-4324-2291","position":2,"is_corresponding":false},{"id":51374,"name":"Sarah A. Zhao","orcid":"0009-0008-6068-5693","position":3,"is_corresponding":false},{"id":85740,"name":"Federica Mosti","orcid":"0000-0001-6317-9093","position":4,"is_corresponding":false},{"id":85741,"name":"Michael C. Thomas","orcid":"0000-0002-6838-646X","position":5,"is_corresponding":false},{"id":85742,"name":"Ravi Karra","orcid":"0000-0001-6741-285X","position":6,"is_corresponding":false},{"id":85743,"name":"Debra L. Silver","orcid":"0000-0001-9189-844X","position":7,"is_corresponding":false},{"id":14693,"name":"Sharon L. R. Kardia","orcid":"0000-0002-9853-3379","position":8,"is_corresponding":false},{"id":41921,"name":"Craig B. Lowe","orcid":"0000-0002-6838-1976","position":9,"is_corresponding":false},{"id":51322,"name":"Yanting Luo","orcid":"0000-0003-0439-6164","position":0,"is_corresponding":true}],"reference_count":117,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":"41279559","pmcid":"PMC12633414","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":"green","license":"cc-by","views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":52.5,"fair_a":42.5,"fair_i":25.0,"fair_r":33.3333,"fair_zscore":-0.6222,"fair_rationale":{"fair_score":38.33,"has_llm":true,"dimensions":{"F":{"name":"Findable","score":52.5,"criteria":[{"key":"f_has_doi","label":"Has a persistent DOI","kind":"deterministic","weight":1.0,"fraction":1.0,"signal":"DOI present","rationale":null},{"key":"f_repository_presence","label":"Indexed in repositories / literature DBs","kind":"deterministic","weight":1.0,"fraction":1.0,"signal":"datacite=0, pmcid=True, pmid=True","rationale":null},{"key":"f_persistent_ids","label":"Resolvable scholarly identifiers (OpenAlex)","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"no OpenAlex id","rationale":null},{"key":"f_metadata_richness","label":"Rich, machine-readable metadata","kind":"llm","weight":1.0,"fraction":0.25,"signal":null,"rationale":"The paper provides a DOI and author metadata but lacks machine-readable structured metadata like schema.org or DataCite."}]},"A":{"name":"Accessible","score":42.5,"criteria":[{"key":"a_open_access","label":"Open Access / files deposited","kind":"deterministic","weight":1.5,"fraction":1.0,"signal":"Open Access","rationale":null},{"key":"a_retrievable","label":"Free full text retrievable","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"0 OA location(s)","rationale":null},{"key":"a_access_protocol","label":"Clear data/code access protocol","kind":"llm","weight":1.0,"fraction":0.25,"signal":null,"rationale":"No explicit repository or download link for the 20-way alignment or HAQER sets is stated; only a vague mention of 'available' resources."}]},"I":{"name":"Interoperable","score":25.0,"criteria":[{"key":"i_linked_data","label":"Linked datasets / DataCite relations","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"linked_datasets=0, datacite=0","rationale":null},{"key":"i_standard_ids","label":"References data via standard accessions","kind":"deterministic","weight":1.0,"fraction":0.0,"signal":"accessions=0, trials=0","rationale":null},{"key":"i_standards","label":"Standard formats, vocabularies & identifiers","kind":"llm","weight":1.0,"fraction":0.5,"signal":null,"rationale":"Uses standard genomic formats (FASTA, BED) and references T2T assemblies but does not specify controlled vocabularies or persistent identifiers for data elements."}]},"R":{"name":"Reusable","score":33.33,"criteria":[{"key":"r_license","label":"Clear, open reuse license","kind":"deterministic","weight":1.5,"fraction":0.0,"signal":"no license","rationale":null},{"key":"r_downloads","label":"Demonstrated reuse (downloads)","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"downloads=0","rationale":null},{"key":"r_version","label":"Versioned / maintained","kind":"deterministic","weight":0.5,"fraction":0.0,"signal":"no version chain","rationale":null},{"key":"r_dataset","label":"Classified as a data resource","kind":"deterministic","weight":0.5,"fraction":1.0,"signal":"is_dataset","rationale":null},{"key":"r_reusability","label":"Data-availability statement, license & reproducibility","kind":"llm","weight":2.0,"fraction":0.5,"signal":null,"rationale":"States a Creative Commons Attribution 4.0 license and mentions code availability but lacks a formal data-availability statement or explicit reproducibility instructions."}]}},"suggestions":["Provide a persistent data repository link (e.g., Zenodo, Figshare) for the 20-way alignment and HAQER coordinates.","Include machine-readable metadata (e.g., JSON-LD) in the HTML header for automated indexing.","Specify the exact software versions and parameters used for alignment and HAQER detection.","Deposit all code and scripts in a version-controlled repository with a DOI.","Add a formal data-availability statement in the manuscript text."],"model":"deepseek/deepseek-v4-flash","agent_version":"fair_agent_v1","fulltext_source":"epmc_xml"},"fair_model":"deepseek/deepseek-v4-flash","fair_agent_version":"fair_agent_v1","fair_fulltext_source":"epmc_xml","fair_has_llm":true,"fair_computed_at":"2026-06-17T22:59:37.653654Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}