A human transcriptomic deletion links cortical expansion and cancer
- 1Stanford University
Abstract
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 HMMR, 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 in vitro. Introducing the human HMMR 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 HMMR isoform in carcinoma progression, our results suggest that evolution of HMMR 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.
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BibTeX
@misc{starr2026human,
title = {{A human transcriptomic deletion links cortical expansion and cancer}},
author = {A. L. Starr and A. Villalba and J. Rever and Y. Chen and F. M. Pauler and L. Magtanong and C. A. Maxwell and S. Hippenmeyer and H. B. Fraser},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752114},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752114v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - A human transcriptomic deletion links cortical expansion and cancer
AU - A. L. Starr
AU - A. Villalba
AU - J. Rever
AU - Y. Chen
AU - F. M. Pauler
AU - L. Magtanong
AU - C. A. Maxwell
AU - S. Hippenmeyer
AU - H. B. Fraser
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752114
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752114v1
AB - 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 HMMR, 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 in vitro. Introducing the human HMMR 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 HMMR isoform in carcinoma progression, our results suggest that evolution of HMMR 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.
ER -