Gene expansions contributing to human brain evolution
Authors: Soto Daniela C. , Uribe-Salazar José M. , Kaya Gulhan , Valdarrago Ricardo , Sekar Aarthi , Haghani Nicholas K. , Hino Keiko , La Gabriana N. , Mariano Natasha Ann F. , Ingamells Cole , Baraban Aidan E. , Turner Tychele N. , Green Eric D. , Simó Sergi , Quon Gerald , Andrés Aida M. , Dennis Megan Y. 
Published: September 2024

Genomic drivers of human-specific neurological traits remain largely undiscovered. Duplicated genes expanded uniquely in the human lineage likely contributed to brain evolution, including the increased complexity of synaptic connections between neurons and the dramatic expansion of the neocortex. Discovering duplicate genes is challenging because the similarity of paralogs makes them prone to sequence-assembly errors. To mitigate this issue, we analyzed a complete telomere-to-telomere human genome sequence (T2T-CHM13) and identified 213 duplicated gene families likely containing human-specific paralogs (>98% identity). Positing that genes important in universal human brain features should exist with at least one copy in all modern humans and exhibit expression in the brain, we narrowed in on 362 paralogs with at least one copy across thousands of ancestrally diverse genomes and present in human brain transcriptomes. Of these, 38 paralogs co-express in gene modules enriched for autism-associated genes and potentially contribute to human language and cognition. We narrowed in on 13 duplicate gene families with human-specific paralogs that are fixed among modern humans and show convincing brain expression patterns. Using long-read DNA sequencing revealed hidden variation across 200 modern humans of diverse ancestries, uncovering signatures of selection not previously identified, including possible balancing selection ofCD8B. To understand the roles of duplicated genes in brain development, we generated zebrafish CRISPR “knockout” models of nine orthologs and transiently introduced mRNA-encoding paralogs, effectively “humanizing” the larvae. Morphometric, behavioral, and single-cell RNA-seq screening highlighted, for the first time, a possible role forGPR89Bin dosage-mediated brain expansion andFRMPD2Bfunction in altered synaptic signaling, both hallmark features of the human brain. Our holistic approach provides important insights into human brain evolution as well as a resource to the community for studying additional gene expansion drivers of human brain evolution.

Abstract (short)

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, we used long-read DNA sequencing of hundreds of modern humans to reveal previously hidden signatures of selection. To understand their 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 new genes in possibly contributing to hallmark features of the human brain:GPR89Bin dosage-mediated brain expansion andFRMPD2Bin altered synapse signaling. Our holistic approach provides new insights and a comprehensive resource for studying gene expansion drivers of human brain evolution.