Fixed human pangenome sequences reveal origins of common human traits

Abstract Humans possess human-specific traits 1,2 such as spoken language and lineage-specific traits such as ape-specific taillessness 3,4 . 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 sampling 5–16 . 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/NOVA1 17,18 amino acid substitutions linked to human spoken language and TBXT transposable element insertion contributing to ape taillessness 3,4 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 elements 19–22 identified putative regulatory sequences specific to humans and linked to human-specific traits like hair reduction 23,24 and brain transcriptome patterning 25 . 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.