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

What genes and regulatory sequences differentiate humans from apes and from archaic humans, which share highly similar genomes but show distinct phenotypes, has puzzled researchers for decades. Previous studies have examined species-specific protein-coding genes and related regulatory sequences, revealing that birth, loss, and changes in these genes and sequences can drive speciation and evolution. However, investigations of species-specific lncRNA genes and the related regulatory sequences, which critically determine epigenetic regulation, remain very limited. We identified human-specific (HS) lncRNAs from GENCODE-annotated human lncRNAs, predicted their DNA binding domains (DBDs) and binding sites (DBSs) genome-wide, analyzed the DBS sequences in modern humans (CEU, CHB, and YRI), archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and chimpanzees, and analyzed how HS lncRNAs and DBSs influence gene expression in modern and archaic humans. Our results suggest that HS lncRNAs and their DBSs have substantially reshaped gene expression. This reshaping has evolved continuously from archaic to modern humans, enabling humans to adapt to new environments and lifestyles, promoting brain evolution, and also resulting in differences among modern humans. Further analyses of HS TFs and their DBSs obtained results suggesting that HS lncRNAs may contribute more significantly than HS TFs to human evolution.