Human-specific gene expansions contribute to brain evolution

Daniela C Soto¹, José M Uribe-Salazar¹, Gulhan Kaya¹, Ricardo Valdarrago², Aarthi Sekar¹, Nicholas K Haghani¹, Keiko Hino³, Gabriana La¹, Natasha Ann F Mariano⁴, Cole Ingamells¹, Aidan Baraban¹, Zoeb Jamal¹, Tychele N Turner⁵, Eric D Green⁶, Sergi Simó³, Gerald Quon⁷, Aida M Andrés⁸, Megan Y Dennis⁹

Affiliations

¹ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA.
² Department of Molecular & Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
³ Department of Cell Biology & Human Anatomy, University of California, Davis, Davis, CA 95616, USA.
⁴ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA; Postbaccalaureate Research Education Program, University of California, Davis, Davis, CA 95616, USA.
⁵ Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Genome Center, University of California, Davis, Davis, CA 95616, USA; Department of Molecular & Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
⁸ UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College, London, Cambridge WC1E 6BT, UK.
⁹ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA. Electronic address: mydennis@ucdavis.edu.

PMID: 40695280
PMCID: PMC12313184 (available on 2026-07-21)
DOI: 10.1016/j.cell.2025.06.037

Human-specific gene expansions contribute to brain evolution

Daniela C Soto et al. Cell. 2025.

. 2025 Sep 18;188(19):5363-5383.e22.

doi: 10.1016/j.cell.2025.06.037. Epub 2025 Jul 21.

Authors

Affiliations

¹ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA.
² Department of Molecular & Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
³ Department of Cell Biology & Human Anatomy, University of California, Davis, Davis, CA 95616, USA.
⁴ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA; Postbaccalaureate Research Education Program, University of California, Davis, Davis, CA 95616, USA.
⁵ Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Genome Center, University of California, Davis, Davis, CA 95616, USA; Department of Molecular & Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
⁸ UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College, London, Cambridge WC1E 6BT, UK.
⁹ Department of Biochemistry & Molecular Medicine, MIND Institute, University of California, Davis, Davis, CA 95616, USA; Genome Center, University of California, Davis, Davis, CA 95616, USA. Electronic address: mydennis@ucdavis.edu.

PMID: 40695280
PMCID: PMC12313184 (available on 2026-07-21)
DOI: 10.1016/j.cell.2025.06.037

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.

Keywords: brain; copy-number variation; gene duplications; gene expression; human evolution; natural selection; neurodevelopment; segmental duplications; sequencing; zebrafish.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Human-specific gene expansions contribute to brain evolution.
Soto DC, Uribe-Salazar JM, Kaya G, Valdarrago R, Sekar A, Haghani NK, Hino K, La G, Mariano NAF, Ingamells C, Baraban A, Jamal Z, Turner TN, Green ED, Simó S, Quon G, Andrés AM, Dennis MY. Soto DC, et al. bioRxiv [Preprint]. 2025 Jun 25:2024.09.26.615256. doi: 10.1101/2024.09.26.615256. bioRxiv. 2025. Update in: Cell. 2025 Sep 18;188(19):5363-5383.e22. doi: 10.1016/j.cell.2025.06.037. PMID: 39386494 Free PMC article. Updated. Preprint.

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Human-specific gene expansions contribute to brain evolution

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Human-specific gene expansions contribute to brain evolution

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