Study Overview.

(A) The relationships between the 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) DBSs’ mean length and binding affinity. (C) The target genes and transcripts of 66 HS lncRNAs. (D) The targeting relationships between HS lncRNAs. (E) The sequence distances of DBSs (the top 40%) from modern humans to chimpanzees and archaic humans. (F) The impacts of interactions between HS lncRNAs and DBSs on gene expression in GTEx tissues.

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 percentage distribution of correlated HS lncRNA-target transcript pairs across GTEx tissues and organs. Higher percentages of correlated pairs are in the brain than in other tissues and organs. (B) The distribution of significantly changed DBSs in HS lncRNA-target transcript pairs across GTEx tissues and organs between archaic and modern humans. Orange, red, and dark red indicate significant DBS changes from Denisovans (D), Altai Neanderthals and Denisovans (AD), and all of the three archaic humans (ADV). DBSs in HS lncRNA-target transcript pairs correlated 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 rewired gene expression by HS lncRNAs in the frontal cortex (BA9).

(A) Genes expressed in the frontal cortex are enriched for HS lncRNAs’ target genes and neurodevelopment-related pathways. Squares indicate HS lncRNAs; dots indicate gene modules (Module_1 and Module_2 are illustrated); colors indicate enriched KEGG pathways. (B) Comparison of modules of the same genes in humans and macaques (indicated by H and M). In each pair of modules, green dots, and blue dots denote human genes and their orthologues in the corresponding positions, and lines indicate correlation. Correlated expression is more prominent in humans than in macaques.