Fixed human pangenome sequences reveal origins of common human traits

Humans possess human-specific traits1,2 such as spoken language and lineage-specific traits such as ape-specific taillessness3,4. Previous efforts to identify the DNA sequences responsible for such human traits were limited by necessary accommodations for poor genome assembly quality and lack of population genomic sampling5-16. Here, we implement new algorithms that combine the near-complete human reference pangenome alignment with a new near-complete simian cross-species alignment to define human- and lineage-specific DNA sequences fixed across human haplotypes. Previously reported FOXP2/NOVA117,18 amino acid substitutions linked to human spoken language and TBXT transposable element insertion contributing to ape taillessness3,4 were unique to their respective clades and fixed in sampled humans. In contrast, widely used sets of candidate human-mutated loci showed limited enrichment for either human specificity or fixation. Integration with candidate cis-regulatory elements19-22 identified putative regulatory sequences specific to humans and linked to human-specific traits like hair reduction23,24 and brain transcriptome patterning25. Although brain-associated fixed regulatory changes were present in all lineages, enrichment for spoken language was human-specific and enrichment for receptive language was ape-specific. This study provides a new pangenome-aware comparative framework and catalogs of candidate genomic loci to trace the evolutionary origins of common human traits and disease risks.