{"dataavailabilitystatement":"Bulk and single cell RNA-sequencing data generated in this study have been uploaded to the\r\nGene expression omnibus (GEO) with accessions GSE346330 and GSE346338 respectively. \r\nBulk RNA-seq data used to identify htCONDELs are publicly available with the following GEO\r\naccessions: GSE146481, GSE144825, and GSE232949. Splicing data from additional species\r\nwas downloaded from https://apps.kaessmannlab.org/alternative-splicing/ and GTEx v10 sQTL\r\ndata was downloaded from https://gtexportal.org/api/v2/association/dynsqtl.\r\nCode for this study is available at: https://github.com/astarr97/Splicing. Code to perform the\r\nalignment of RNA-seq data from hybrid cells is available at: https://github.com/banwang27/multi1216 celltypes. ","date_created":"2026-10-01T07:21:25Z","acknowledgement":"We would like to acknowledge the MSKCC transgenic mouse core facility for generating\r\nhumanized mice, as well as Nancy Du, Xiang Chen, and other Du lab members for mouse\r\nbreeding and genotyping. This research was supported by the Scientific Service Units (SSU) of\r\nIST Austria through resources provided by the Imaging and Optics- (IOF), Lab Support- (LSF)\r\nand Preclinical Facilities (PCF). We would also like to thank Fee Wielath and Kerstin Feistel for\r\nhelpful discussions. Some figures were made with biorender. Work in the Fraser laboratory is supported by NIH grants R01HG012285 and R35GM156526.\r\nWork in the Hippenmeyer laboratory is supported by ISTA institutional funds and FWF Cluster of\r\nExcellence COE16 (10.55776/COE16) to S.H. Work in the Maxwell laboratory is supported by\r\nthe National Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2019-\r\n06215 and 2025-05766) and the Canadian Institutes of Health Research (F24-00975). J.R. is\r\nsupported by a Canada Graduate Research Scholarship-Doctoral (612468 - 2026) from\r\nNSERC. A.L.S. is supported by the FutureHouse postdoctoral fellowship program and the Kavli\r\nFoundation. ","main_file_link":[{"url":"https://doi.org/10.64898/2026.09.16.752114","open_access":"1"}],"author":[{"full_name":"Starr, Alexander L.","first_name":"Alexander L.","last_name":"Starr"},{"full_name":"Villalba Requena, Ana","first_name":"Ana","id":"68cb85a0-39f7-11eb-9559-9aaab4f6a247","last_name":"Villalba Requena","orcid":"0000-0002-5615-5277"},{"full_name":"Rever, Jenna","last_name":"Rever","first_name":"Jenna"},{"last_name":"Chen","first_name":"Yuwei","id":"7f9e985d-7380-11f0-bf20-b4121a7bdcbc","full_name":"Chen, Yuwei"},{"first_name":"Florian","id":"48EA0138-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7462-0048","last_name":"Pauler","full_name":"Pauler, Florian"},{"first_name":"Leslie","last_name":"Magtanong","full_name":"Magtanong, Leslie"},{"first_name":"Christopher A.","last_name":"Maxwell","full_name":"Maxwell, Christopher A."},{"full_name":"Hippenmeyer, Simon","id":"37B36620-F248-11E8-B48F-1D18A9856A87","first_name":"Simon","orcid":"0000-0003-2279-1061","last_name":"Hippenmeyer"},{"last_name":"Fraser","first_name":"Hunter B.","full_name":"Fraser, Hunter B."}],"corr_author":"1","researchdata_availability":"yes","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"PreCl"}],"type":"preprint","doi":"10.64898/2026.09.16.752114","status":"public","OA_type":"green","abstract":[{"lang":"eng","text":"Alternative splicing represents a major source of potential evolutionary novelty in protein sequence. Despite this, relatively few studies have investigated the functional impacts of human-specific alternative splicing. Here, we analyze RNA-sequencing data from nine iPSC-derived cell types and identify dozens of human transcriptomic conserved deletions (htCONDELs): evolutionary divergence in splicing that leads to the partial or full removal of conserved protein-coding sequence from the human transcriptome. We investigated one example in detail: an htCONDEL in the gene\r\nHMMR\r\n                  , which encodes a centrosomal protein that binds microtubules and regulates mitosis. We found that this htCONDEL, which produces a human-specific isoform lacking a conserved microtubule-binding domain, enables cells to flexibly divide with a broader range of mitotic spindle orientations\r\n      in vitro\r\n                  . Introducing the human\r\n                  HMMR\r\n                  isoform into mice similarly alters the orientation of cell division in the developing neocortex and increases the production of outer radial glia-like cells, the expansion of which played an essential role in increasing human brain size. Combined with previous work implicating the same\r\n                 HMMR\r\n                  isoform in carcinoma progression, our results suggest that evolution of\r\nHMMR\r\n                  splicing in humans increased plasticity in cell division, potentially leading to tradeoffs between advantageous effects on brain development and deleterious effects on cancer risk later in life."}],"title":"A human transcriptomic deletion links cortical expansion and cancer","date_updated":"2026-10-07T08:50:37Z","day":"18","language":[{"iso":"eng"}],"oa_version":"Preprint","external_id":{"biorxivid":["10.64898/2026.09.16.752114"]},"year":"2026","publication":"bioRxiv","_id":"23011","fulldoi":"https://doi.org/10.64898/2026.09.16.752114","supplementarymaterial":"yes","oa":1,"project":[{"_id":"9e227eae-b037-11f1-b1e2-fb7da760c1dd","name":"Neuronal circuits in health and disease (Hippenmeyer)","grant_number":"COE16"}],"biorxivid":1,"OA_place":"repository","citation":{"ama":"Starr AL, Villalba Requena A, Rever J, et al. A human transcriptomic deletion links cortical expansion and cancer. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.64898/2026.09.16.752114\">10.64898/2026.09.16.752114</a>","chicago":"Starr, Alexander L., Ana Villalba Requena, Jenna Rever, Yuwei Chen, Florian Pauler, Leslie Magtanong, Christopher A. Maxwell, Simon Hippenmeyer, and Hunter B. Fraser. “A Human Transcriptomic Deletion Links Cortical Expansion and Cancer.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.64898/2026.09.16.752114\">https://doi.org/10.64898/2026.09.16.752114</a>.","ista":"Starr AL, Villalba Requena A, Rever J, Chen Y, Pauler F, Magtanong L, Maxwell CA, Hippenmeyer S, Fraser HB. A human transcriptomic deletion links cortical expansion and cancer. bioRxiv, <a href=\"https://doi.org/10.64898/2026.09.16.752114\">10.64898/2026.09.16.752114</a>.","apa":"Starr, A. L., Villalba Requena, A., Rever, J., Chen, Y., Pauler, F., Magtanong, L., … Fraser, H. B. (n.d.). A human transcriptomic deletion links cortical expansion and cancer. <i>bioRxiv</i>. <a href=\"https://doi.org/10.64898/2026.09.16.752114\">https://doi.org/10.64898/2026.09.16.752114</a>","mla":"Starr, Alexander L., et al. “A Human Transcriptomic Deletion Links Cortical Expansion and Cancer.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.64898/2026.09.16.752114\">10.64898/2026.09.16.752114</a>.","short":"A.L. Starr, A. Villalba Requena, J. Rever, Y. Chen, F. Pauler, L. Magtanong, C.A. Maxwell, S. Hippenmeyer, H.B. Fraser, BioRxiv (n.d.).","ieee":"A. L. Starr <i>et al.</i>, “A human transcriptomic deletion links cortical expansion and cancer,” <i>bioRxiv</i>. ."},"das_tickbox":"1","department":[{"_id":"SiHi"}],"article_processing_charge":"No","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"submitted","date_published":"2026-09-18T00:00:00Z","month":"09"}