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bioRxiv · 10.1101/2024.09.26.615256

Gene expansions contributing to human brain evolution

Soto, D. C.·Uribe-Salazar, J. M.·Kaya, G.·Valdarrago, R.·Sekar, A.·Haghani, N. K.·Hino, K.·La, G. N.·Mariano, N. A. F.·Ingamells, C.·Baraban, A. E.·Turner, T. N.·Green, E. D.·Simo, S.·Quon, G.·Andres, A.·Dennis, M. Y.
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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.

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Soto, D. C., Uribe-Salazar, J. M., Kaya, G., Valdarrago, R., Sekar, A., Haghani, N. K., Hino, K., La, G. N., Mariano, N. A. F., Ingamells, C., Baraban, A. E., Turner, T. N., Green, E. D., Simo, S., Quon, G., Andres, A., Dennis, M. Y.. 2024-09-26. Gene expansions contributing to human brain evolution. https://doi.org/10.1101/2024.09.26.615256

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