Complete telomere-to-telomere genome revealed 213 human-specific gene families. 362 paralogs present in all modern human genomes and brain transcriptomes. Long-read sequencing of hundreds of humans uncovered selection signatures including CD8B. Zebrafish CRISPR knockouts of nine orthologs tested paralog functions. GPR89B paralog causes dosage-mediated brain expansion in humanized zebrafish larvae. FRMPD2B paralog alters synapse signaling in humanized zebrafish. Duplicated genes expanded in human lineage contribute to brain evolution. Paralogs express highly in developing human brain. Segmental duplications harbor these human-unique genes. Assembly errors previously hid these duplications. Resource lists top candidates for human brain features.