Soto, Daniela C;
Uribe-Salazar, José M;
Kaya, Gulhan;
Valdarrago, Ricardo;
Sekar, Aarthi;
Haghani, Nicholas K;
Hino, Keiko;
... Dennis, Megan Y; + view all
(2025)
Human-specific gene expansions contribute to brain evolution.
Cell
10.1016/j.cell.2025.06.037.
(In press).
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Abstract
Duplicated genes expanded in the human lineage likely contributed to brain evolution, yet challenges exist in their discovery due to sequence-assembly errors. We used a complete telomere-to-telomere genome sequence to identify 213 human-specific gene families. From these, 362 paralogs were found in all modern human genomes tested and brain transcriptomes, making them top candidates contributing to human-universal brain features. Choosing a subset of paralogs, long-read DNA sequencing of hundreds of modern humans revealed previously hidden signatures of selection, including for T cell marker CD8B. To understand roles in brain development, we generated zebrafish CRISPR “knockout” models of nine orthologs and introduced mRNA-encoding paralogs, effectively “humanizing” larvae. Our findings implicate two genes in possibly contributing to hallmark features of the human brain: GPR89B in dosage-mediated brain expansion and FRMPD2B in altered synapse signaling. Our holistic approach provides insights and a comprehensive resource for studying gene expansion drivers of human brain evolution.
| Type: | Article |
|---|---|
| Title: | Human-specific gene expansions contribute to brain evolution |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cell.2025.06.037 |
| Publisher version: | https://doi.org/10.1016/j.cell.2025.06.037 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. It is made available under a under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | segmental duplications, gene duplications, human evolution, brain, neurodevelopment, sequencing, zebrafish, copy-number variation, gene expression, natural selection |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213253 |
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