Study overview.

(A) The relationships between chimpanzees, the three archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and the three modern human populations, with dashed lines indicating the phylogenetic distances from modern humans based on related studies. Based on the left-top icons, the DBS in B2M lacks a counterpart in chimpanzees; the DBS in ABL2 has great differences between archaic and modern humans; the DBS in IRNAR1 is polymorphic in modern humans (red letters indicate tissue-specific eQTLs or population-specific mutations). (B) The mean length and affinity of strong DBSs. (C) Numbers of target genes and target transcripts of HS lncRNAs. (D) An illustrative figure showing the targeting relationships between HS lncRNAs. (E) The sequence distances of DBSs (the top 40%) from modern humans to chimpanzees and archaic humans. (F) An illustrative figure showing the impacts of HS lncRNA-target transcript on gene expression in GTEx tissues (see Supplementary Note 2 and Figure 3).

Genes with DBSs that have largest affinity values and mostly changed sequence distances (from modern humans to archaic humans and chimpanzees).

GO terms generated by different gene sets with large and small DBS distances from humans to chimpanzees and Altai Neanderthals.

Shown are the presence and absence of GO terms highly related to human evolution. (A) Genes sorted by DBS distance from humans to chimpanzees and to Altai Neanderthals. Left: The top 25% of genes. Right: The bottom 25% of genes. (B) The intersections of the top 50% and bottom 50% of genes (with DBS distances from humans to chimpanzees and to Altai Neanderthals) and genes with significant ASE (p-adj<0.01 and |LFC|>0.5).

Genes with DBSs that are most polymorphic and have mostly changed sequence distances from humans to archaic humans and chimpanzees.

The impact of HS lncRNA-DBS interaction on gene expression in GTEx tissues and organs.

(A) The distribution of the percentage of HS lncRNA-target transcript pairs with correlated expression across GTEx tissues and organs. Higher percentages of correlated pairs are in brain regions than in other tissues and organs. (B) The distribution of significantly changed DBSs (in terms of sequence distance) in HS lncRNA-target transcript pairs across GTEx tissues and organs between archaic and modern humans. Orange, red, and dark red indicate significant changes from Denisovans (D), Altai Neanderthals and Denisovans (AD), and all three archaic humans (ADV). DBSs in HS lncRNA-target transcript pairs with correlated expression in seven brain regions (in dark red) have changed significantly and consistently since the Altai Neanderthals, Denisovans, and Vindija Neanderthals (one-sided two-sample Kolmogorov-Smirnov test, significant changes determined by FDR <0.001).

Human-specifically reshaped gene expression by HS lncRNAs in the frontal cortex (BA9).

(A) Genes expressed in the human frontal cortex are enriched for HS lncRNAs’ target genes and neurodevelopment-related pathways. Squares, dots, and colors indicate HS lncRNAs, gene modules (Module_1 and Module_2 are illustrated), and enriched KEGG pathways, respectively. (B) Comparison of modules and genes in humans (indicated by H) and macaques (indicated by M). In each pair of modules, green and blue dots denote human genes and their orthologues, and lines between dots indicate correlated expression. Many orthologous genes in macaques (displayed at the corresponding positions) are not in the modules, and correlated expression is more prominent in humans than in macaques.