---
OA_place: repository
OA_type: green
_id: '23011'
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."
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: PreCl
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. "
article_processing_charge: No
author:
- first_name: Alexander L.
full_name: Starr, Alexander L.
last_name: Starr
- first_name: Ana
full_name: Villalba Requena, Ana
id: 68cb85a0-39f7-11eb-9559-9aaab4f6a247
last_name: Villalba Requena
orcid: 0000-0002-5615-5277
- first_name: Jenna
full_name: Rever, Jenna
last_name: Rever
- first_name: Yuwei
full_name: Chen, Yuwei
id: 7f9e985d-7380-11f0-bf20-b4121a7bdcbc
last_name: Chen
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Leslie
full_name: Magtanong, Leslie
last_name: Magtanong
- first_name: Christopher A.
full_name: Maxwell, Christopher A.
last_name: Maxwell
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
- first_name: Hunter B.
full_name: Fraser, Hunter B.
last_name: Fraser
biorxivid: 1
citation:
ama: Starr AL, Villalba Requena A, Rever J, et al. A human transcriptomic deletion
links cortical expansion and cancer. bioRxiv. doi:10.64898/2026.09.16.752114
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. bioRxiv. https://doi.org/10.64898/2026.09.16.752114
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.”
BioRxiv, n.d. https://doi.org/10.64898/2026.09.16.752114.
ieee: A. L. Starr et al., “A human transcriptomic deletion links cortical
expansion and cancer,” bioRxiv. .
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, 10.64898/2026.09.16.752114.
mla: Starr, Alexander L., et al. “A Human Transcriptomic Deletion Links Cortical
Expansion and Cancer.” BioRxiv, doi:10.64898/2026.09.16.752114.
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.).
corr_author: '1'
das_tickbox: '1'
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
date_published: 2026-09-18T00:00:00Z
date_updated: 2026-10-07T08:50:37Z
day: '18'
department:
- _id: SiHi
doi: 10.64898/2026.09.16.752114
external_id:
biorxivid:
- 10.64898/2026.09.16.752114
fulldoi: https://doi.org/10.64898/2026.09.16.752114
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.64898/2026.09.16.752114
month: '09'
oa: 1
oa_version: Preprint
project:
- _id: 9e227eae-b037-11f1-b1e2-fb7da760c1dd
grant_number: COE16
name: Neuronal circuits in health and disease (Hippenmeyer)
publication: bioRxiv
publication_status: submitted
researchdata_availability: yes
status: public
supplementarymaterial: yes
title: A human transcriptomic deletion links cortical expansion and cancer
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2026'
...