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PreprintCited by 25Genomic variations and chromosomal abnormalitiesChromosomal and Genetic VariationsGenomics and Phylogenetic Studies

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Human-specific gene expansions contribute to brain evolution

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Soto, Daniela C., Uribe-Salazar, José M., Kaya, Gulhan, Valdarrago, Ricardo, Sekar, Aarthi, Haghani, Nicholas K., Hino, Keiko, La, Gabriana, Mariano, Natasha Ann F., Ingamells, Cole, Baraban, Aidan, Jamal, Zoeb, Turner, Tychele N., Green, Eric D., Simó, Sergi, Quon, Gerald, Andrés, Aida M., Dennis, Megan Y.·2024·Cell
DOI 10.1101/2024.09.26.615256PMC PMC11463660

Preprint — published as 10.1016/j.cell.2025.06.037

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Abstract

Summary: 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.

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Metadata

Authors
Soto, D. C., Uribe-Salazar, J. M., Kaya, G., Valdarrago, R., Sekar, A., Haghani, N. K., Hino, K., La, G., Mariano, N. A. F., Ingamells, C., Baraban, A., Jamal, Z., Turner, T. N., Green, E. D., Simó, S., Quon, G., Andrés, A. M., & Dennis, M. Y.
Affiliations
  • University of California, Davis (US)
  • Washington University in St. Louis (US)
  • National Institutes of Health (US)
  • University College London (GB)
Corresponding author
Dennis, Megan Y.
ORCID
Venue
Cell
Publisher
openRxiv
Published
2024-09-26
Volume
188
Issue
19
Pages
5363-5383.e22
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2024.09.26.615256
PMC
PMC11463660
OpenAlex
W4412527149
Cited by
25
References
1
Citations by year
2026: 18 · 2025: 7
FWCI
6.63
Type
journal article
Language
en
Open access
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor)
Locations
  • Cell (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Science Foundation (2145885, 1846559)
  • Wellcome Trust (204841/Z/16/Z)
  • Biotechnology and Biological Sciences Research Council (BB/WW007703/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
human brain evolution, gene family expansion, gene duplication, paralogs, telomere-to-telomere genome assembly, long-read sequencing, positive selection, dosage compensation, brain development

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