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
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.
Department of Molecular & Cellular Biology, University of California, Davis, Davis, CA 95616, USA.
Cell. 2025 Jul 18. doi: 10.1016/j.cell.2025.06.037.
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.
在人类谱系中扩增的重复基因可能对大脑进化有贡献，但由于序列组装错误，它们的发现存在挑战。我们使用了一个完整的端粒到端粒的基因组序列来鉴定213个人类特异性基因家族。从这些家族中，在所有测试的现代人类基因组和大脑转录组中发现了362个旁系同源基因，使它们成为促成人类普遍大脑特征的首要候选基因。选择一部分旁系同源基因，对数百名现代人进行长读长DNA测序，揭示了以前隐藏的选择特征，包括T细胞标志物CD8B的选择特征。为了了解这些基因在大脑发育中的作用，我们构建了9个直系同源基因的斑马鱼CRISPR“敲除”模型，并引入了编码旁系同源基因的mRNA，有效地使幼虫“人源化”。我们的研究结果表明，有两个基因可能对人类大脑的标志性特征有贡献：GPR89B在剂量介导的大脑扩张中起作用，FRMPD2B在突触信号改变中起作用。我们的整体方法为研究人类大脑进化的基因扩张驱动因素提供了见解和全面的资源。
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