Study Overview.

(A) The relationships between chimpanzees, the three archaic humans (Altai Neanderthals, Denisovans, and Vindija Neanderthals), and the three modern human populations. Dashed lines indicate the phylogenetic distances from modern humans to archaic humans and chimpanzees. Genes and DBSs have the following implications: 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 highly polymorphic in modern humans. Red letters in DBSs indicate tissue-specific eQTLs or population-specific favored mutations. (B) The mean length and binding affinity of strong DBSs. (C) Number of target genes and transcripts of the 66 HS lncRNAs. (D) The illustrative figure shows the targeting relationships between HS lncRNAs (see the full figure in Supplementary Note 2). (E) The sequence distances of DBSs (the top 40%) from modern humans to chimpanzees and archaic humans. (F) The illustrative figure shows the GTEx tissues used to investigate the impacts of HS lncRNA-target transcript pairs on gene expression (see the full figure in Figure 3).

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

1256 target genes whose DBSs have the largest distances from modern humans to chimpanzees and Altai Neanderthals are enriched in different Biological Processes GO terms.

Upon significance threshold = 0.05 (Benjamini-Hochberg FDR), the two gene sets in chimpanzees and Altai Neanderthals are enriched in 199 and 409 GO terms (50<terms size<1000), respectively. Shared GO terms are color-marked. Left: Top GO terms enriched in genes in chimpanzees. Right: Top GO terms enriched in genes in Altai Neanderthals.

Genes with most polymorphic DBSs and DBSs with mostly changed sequence distances from modern 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. Note that many orthologous genes in macaques are not in the modules but displayed in the corresponding positions, and correlated expression is more prominent in humans than in macaques.