{"doi":"10.1101/2021.09.14.460388","title":"The genetic basis of tail-loss evolution in humans and apes","abstract":"The loss of the tail is one of the main anatomical evolutionary changes to have occurred along the lineage leading to humans and to the “anthropomorphous apes” 1,2 . This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans 3–5 . Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes 6–8 , and enable the search for hominoid-specific genetic elements controlling tail development 9 . Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual Alu element into the genome of the hominoid ancestor. We demonstrate that this Alu element – inserted into an intron of the TBXT gene (also called T or Brachyury 10–12 ) – pairs with a neighboring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated a mouse model that mimics the expression of human TBXT products by expressing both full-length and exon-skipped isoforms of the mouse TBXT ortholog. We found that mice with this genotype exhibit the complete absence of a tail or a shortened tail, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype, albeit with incomplete penetrance. We further noted that mice homozygous for the exon-skipped isoforms exhibited embryonic spinal cord malformations, resembling a neural tube defect condition, which affects ∼1/1000 human neonates 13 . We propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defects and that this ancient evolutionary trade-off may thus continue to affect human health today.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213207,"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":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":49799,"name":"Weimin Zhang","orcid":"0000-0002-8836-1438","position":1,"is_corresponding":false},{"id":804542,"name":"Aleksandra Wudzinska","orcid":"0000-0002-3143-7673","position":2,"is_corresponding":false},{"id":109140,"name":"Emily Huang","orcid":"0000-0002-9558-7814","position":3,"is_corresponding":false},{"id":438348,"name":"Ran Brosh","orcid":"0000-0001-9714-8623","position":4,"is_corresponding":false},{"id":700903,"name":"Maayan Pour","orcid":"0000-0003-1997-5193","position":5,"is_corresponding":false},{"id":586074,"name":"Alexander Miller","orcid":"0000-0002-0662-9673","position":6,"is_corresponding":false},{"id":470118,"name":"Jeremy S. Dasen","orcid":"0000-0002-9434-874X","position":7,"is_corresponding":false},{"id":11626,"name":"Matthew T. Maurano","orcid":"0000-0002-2218-8628","position":8,"is_corresponding":false},{"id":455291,"name":"Sang Yong Kim","orcid":"0000-0001-7326-7505","position":9,"is_corresponding":false},{"id":49826,"name":"Jef D. Boeke","orcid":"0000-0001-5322-4946","position":10,"is_corresponding":false},{"id":58388,"name":"Itai Yanai","orcid":"0000-0002-8438-2741","position":11,"is_corresponding":false},{"id":804541,"name":"Bo Xia","orcid":"0000-0003-0929-7253","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-18T23:52:31.378994Z","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":[]}