Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression

What genomic sequences make conserved genes generate divergent expression in closely related species, which may have critically driven human evolution, has puzzled researchers for decades. Genomic studies have examined species-specific gene birth, gene loss, and changes in promoters and transcription factor binding sites, but species-specific epigenetic regulation remains barely explored. This study identified human-specific long noncoding RNAs (lncRNAs) from GENCODE-annotated human lncRNAs, predicted their DNA binding sites (DBSs) genome-wide, analyzed these DBSs and their counterparts in modern humans (CEU, CHB, and YRI), archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and chimpanzees, and analyzed the impact of DBSs on gene expression in modern and archaic humans. The results suggest that human-specific lncRNAs and their DBSs have substantially rewired gene expression human-specifically and that the rewiring has evolved continuously from archaic to modern humans. Rewired gene expression promotes brain development, makes humans adapt to new environments and lifestyles, and causes differences in modern humans. These results uncover a critical dimension of human evolution and underscore the diverse functions of species-specific lncRNAs.