{"doi":"10.21203/rs.3.rs-77798/v1","title":"Opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans","abstract":"Abstract TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in human and nonhuman primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations that altered TCAF copy number and regulation. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. The significant, positive effect of H4 on TCAF2 expression in modern-day humans with candidate associations for hypothyroidism, nerve compression, and diabetes suggests TCAF diversification among hominins potentially in response to cold or dietary adaptations.","journal":"Research Square","year":2020,"id":125832,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9293,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":564308,"name":"Vy Dang","orcid":"0000-0002-8754-4064","position":1,"is_corresponding":false},{"id":24561,"name":"Mitchell R. Vollger","orcid":"0000-0002-8651-1615","position":2,"is_corresponding":false},{"id":51349,"name":"Yafei Mao","orcid":"0000-0002-9648-4278","position":3,"is_corresponding":false},{"id":573273,"name":"Tzu‐Hsueh Huang","orcid":null,"position":4,"is_corresponding":false},{"id":49020,"name":"Philip C. Dishuck","orcid":"0000-0003-2223-9787","position":5,"is_corresponding":false},{"id":327932,"name":"Carl Baker","orcid":null,"position":6,"is_corresponding":false},{"id":290631,"name":"Stuart Cantsilieris","orcid":null,"position":7,"is_corresponding":false},{"id":30887,"name":"Alexandra P. Lewis","orcid":"0000-0002-6195-4786","position":8,"is_corresponding":false},{"id":19706,"name":"Katherine M. Munson","orcid":"0000-0001-8413-6498","position":9,"is_corresponding":false},{"id":573274,"name":"Melanie Scofield","orcid":null,"position":10,"is_corresponding":false},{"id":306912,"name":"AnneMarie E. Welch","orcid":"0000-0002-6103-340X","position":11,"is_corresponding":false},{"id":56431,"name":"Jason G. Underwood","orcid":null,"position":12,"is_corresponding":false},{"id":2125,"name":"Evan E. Eichler","orcid":"0000-0002-8246-4014","position":13,"is_corresponding":false},{"id":289887,"name":"PingHsun Hsieh","orcid":"0000-0001-8294-6227","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:15:19.482428Z","pmid":null,"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":[]}