1. Computational and Systems Biology
  2. Genetics and Genomics

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

  1. Jie Lin
  2. Yujian Wen
  3. Ji Tang
  4. Xuecong Zhang
  5. Huanlin Zhang
  6. Hao Zhu  Is a corresponding author
  1. Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, China
  2. College of Biological and Food Engineering, Guangdong University of Petrochemical Technology, China
  3. Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, China
  4. Guangdong Provincial Key Lab of Single Cell Technology and Application, Southern Medical University, China
https://doi.org/10.7554/eLife.89001.6
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  1. Jie Lin
  2. Yujian Wen
  3. Ji Tang
  4. Xuecong Zhang
  5. Huanlin Zhang
  6. Hao Zhu
(2026)
Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression
eLife 12:RP89001.
https://doi.org/10.7554/eLife.89001.6
  2. Download BibTeX
  3. Download .RIS
27 figures, 8 tables and 2 additional files

Figures

Figure 1
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Study overview.

(A) The relationships between chimpanzees, the three archaic humans, 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 expression quantitative trait loci (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) The illustrative figure shows the targeting relationships between HS lncRNAs (Appendix 2—figure 1). (E) Sequence distances of the top 40% of DBSs from modern humans to chimpanzees and archaic humans. (F) The illustrative figure shows the impacts of HS lncRNA–target transcript on gene expression in GTEx tissues (Figure 2).

Figure 2
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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).

Figure 3
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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 orthologs, 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.

Appendix 1—figure 1
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DBSs of the HS lncRNA RP11-423H2.3 in two genomic regions.

In the upper and lower panels that display two genomic regions, the tracks from top to bottom are DBSs (orange peaks), gene annotation, histone modification signals in cell lines, DNA methylation signals in cell lines, H3K4me3 RawSignal, and MRE CpG signals. DBSs overlap very well with DNA methylation and histone modification signals in multiple cell lines.

Appendix 1—figure 2
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Predicted DBSs and experimentally identified (by CHART-seq) DNA-binding sites of NEAT1 and MALAT1 in two cell lines (West et al., 2014).

DBSs were predicted using the DNA sequences of CHART-seq peaks. 99% and 87% of experimentally identified DNA-binding sites of NEAT1 and MALAT1 overlap with predicted DBSs. (A) Predicted DBSs and experimentally identified DNA-binding sites of NEAT1 in three genomic regions. (B) Predicted DBSs and experimentally identified DNA-binding sites of MALAT1 in three genomic regions.

Appendix 1—figure 3
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Examples of co-localization of DBSs, TEs, and cCREs in the promoter regions of genes.

(A) The DBSs of AC106795.2 in the promoter region of ADARB1. (B) The DBSs of AC106795.2 in the promoter region of CDC42EP1. (C) The DBS of AL008727.1 in the promoter region of CD81. (D) The DBS of AC007876.1 in the promoter region of DIDO1 and GID8.

Appendix 1—figure 4
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The expression change of target genes was significantly larger than that of non-target genes after DBD knockout.

The fold change of gene expression was computed using the edgeR package. The |fold change| distribution of target genes was compared with the |fold change| distribution of non-target genes (one-sided Mann–Whitney test). (A) The knockout of a 157-bp sequence (chr17:80252565–80252721) which contains the DBD of RP13-516M14.1, in the HeLa cell line. (B) The knockout of a 202-bp sequence (chr1:113392603–113392804) which contains the DBD of RP11-426L16.8, in the RKO cell line. (C) The knockout of a 198-bp sequence (chr17:19460524–19460721) which contains the DBD of SNORA59B, in the SK-MES-1 cell line. (D, E) The knockout of the DBD of a wrongly transcribed long noncoding RNA (chr1:156641670–156661464) in the A549 cell line and the HCT116 cell line. (F, G) The knockout of the DBD of a wrongly transcribed long noncoding RNA (chr10:52443915–52455313) in the A549 cell line and the HCT116 cell line. These wrongly transcribed long noncoding RNAs are labeled as ‘MSTRG’ transcripts by the Stringtie package. (H) The knockout of the DBD of a third wrongly transcribed long noncoding RNA in the HCT116 cell line.

Appendix 1—figure 5
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Significant up- and downregulation (|log2(fold change)| >1, FDR <0.1) of target genes after DBD knockout.

(A) RP13-516M14.1. (B) RP11-426L16.8. (C) SNORA59B.

Appendix 2—figure 1
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Potential targeting regulation between HS lncRNAs.

The circle’s brown and green regions indicate promoter and gene body regions. Arrows indicate the direction from the gene body to the promoter regions. The width of the arrows indicates the binding affinity of DBSs, and the sizes of blue dots indicate the number of DBSs of the lncRNA in the genome.

Appendix 2—figure 2
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Some DBSs (indicated by blue bars) are in human-specific genome sequences.

(A–D) The DBSs of RP11-848P1.4 in the genes ADCY2, CTD-3179P9.2, IPO11, and PRKAA1. (E) The DBS of RP11-598D14.1 in the gene NCAPG2.

Appendix 2—figure 3
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Many genes and transcripts contain DBSs for multiple HS lncRNAs.

(A) Left to right: the DBSs of RP11-65G9.1, LA16c-306A4.2, RP13-516M14.1, SNORA59B, RP11-423H2.3, and TTTY8/8B in the A1BG. (B) Left to right: the DBSs of TTTY8/8B, RP4-669L17.10, and RP11-423H2.3 in TLR1. (C) Left to right: the DBSs of LA16c-306A4.2, RP11-423H2.3, RP11-423H2.3, RP1-118J21.25, RP11-706O15.5, and SNORA59B in TMEM210B.

Appendix 2—figure 4
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In the GNAS region, RP11-423H2.3 has a DBS (indicated by the blue bar) wherein a selection signal was detected in CEU and CHB (Tajima’s D = −0.99/–1.13/1.86 in CEU/CHB/YRI, integrated Fst = 0.22), and has another DBS (indicated by the orange bar) wherein a selection signal was detected in YRI (Tajima’s D = 0.25/1.09/–1.17 in CEU/CHB/YRI, integrated Fst = 0.33).
Appendix 2—figure 5
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HS lncRNAs on the Y chromosome often have longer DBSs than HS lncRNAs on the autosomes.

The top panel shows that the DBS of TTTY2/2B in HLA-C (indicated by the blue bar) is longer than the two DBSs of RP11-423H2.3 (indicated by the green bars). The bottom panel shows that the DBS of TTTY8/8B in IFNAR1 (indicated by the blue bar) is longer than the DBS of LINC00279 (indicated by the green bar).

Appendix 2—figure 6
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The linkage disequilibrium (LD) of the key SNP in DBSs of HS lncRNAs in genes on some chromosomes.

(A) The LD of the key SNP in the DBSs of LA16c-306A4.2 in some genes on chromosome 16. (B) The LD of the key SNP in the DBSs of RP11-423H2.3 in some genes on chromosome 1. (C) The LD of the key SNP in the DBSs of SNORA59B in some genes on chromosome 1. (D) The LD of the key SNP in the DBSs of TTTY8B in some genes on chromosome 16.

Appendix 3—figure 1
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Numbers of DBSs with large distances from modern humans to archaic humans and chimpanzees, and from the human ancestor to chimpanzees, archaic humans, and modern humans.

Left: DBSs in 4248, 1256, 2513, and 134 genes have distances >0.034 from modern humans to chimpanzees, Altai Neanderthals, Denisovans, and Vindija Neanderthals. Right: DBSs in 5033, 6908, 9707, 5189, and 5521 genes have distances >0.015 from the ancestor to modern humans, Altai Neanderthals, Denisovans, Vindija Neanderthals, and chimpanzees.

Appendix 3—figure 2
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The most changed DBSs also have large sequence distances between humans and gorillas.

(A) Scatter plot showing the sequence distances between humans and chimpanzees and between humans and gorillas. (B) The scatter plot shows the average sequence distances between humans and chimpanzees, the three archaic humans, and between humans and gorillas. The rho and p values were estimated using the Spearman correlation test.

Appendix 4—figure 1
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Positive selection signals detected by the XP-CLR program in (A) RP11-848P1.4, (B) RP11-598D14.1, and (C) CTD-2291D10.1 in CEU and CHB.
Appendix 4—figure 2
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Favored mutations detected by iSAFE.

Left and right vertical axes indicate iSAFE scores and recombination rate. The purple diamond marks the top-scored mutation. Colors mark linkage disequilibrium (LD) (r2) between the top-scoring mutation and others. The yellow line indicates that mutations above it have a probability of p = 1e−6 to be neutral. The blue curve indicates the position-specific recombination rates. (A) SNPs in RP11-598D14.1. The top-scoring SNP has DAFs of 0.125/0.960/0.922 in YRI/CEU/CHB. (B) SNPs in AC006129.1. The top-scoring SNP has DAFs of 0.134/0.717/0.587 in YRI/CEU/CHB.

Appendix 4—figure 3
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HS lncRNA genes with significantly changed Tajima’s D in CEU, CHB, and YRI.

Negative and positive Tajima’s D scores, which are significantly smaller or larger than the genome-wide background in a population, indicate the signature of positive selection or balancing selection, respectively, in the population.

Appendix 4—figure 4
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The linkage disequilibrium (LD) of SNPs in HS lncRNA genes in CEU, CHB, and YRI.

The red color indicates high LD values. These panels show that LD between SNPs in CEU and CHB in these lncRNA genes is stronger than LD between SNPs in YRI. (A) AC024592.9, (B) AC129929.5, (C) RP11-157B13.7, (D) RP11-277P12.10, (E) CTD-2291D10.1, and (F) CTD-2142D14.1.

Appendix 5—figure 1
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The distributions of DBS sequence distances and promoter sequence distances from modern to archaic humans (right-hand panels illustrating distances >0.005).

A fraction of DBSs has larger distances than promoters.

Appendix 5—figure 2
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The distribution of SNP frequencies (MAF >0.05) in DBSs.
Appendix 6—figure 1
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DBSs have significantly higher eQTL density than promoters.

DBSs and promoters harboring at least one eQTL were used to compute eQTL density and make the comparison. A one-sided Mann–Whitney test was used to compute the p-value.

Appendix 8—figure 1
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The distribution of the percentage of HS TF–target transcript pairs with correlated expression across GTEx tissues and organs (see Figure 3A).
Appendix 8—figure 2
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The distribution of significantly changed DBSs (in terms of sequence distance) in HS TF–target transcript pairs across GTEx tissues and organs between archaic and modern humans.

As in Figure 3B, orange, red, and dark red indicate significant changes from Denisovans (D), Altai Neanderthals and Denisovans (AD), and all three archaic humans (ADV).

Appendix 9—figure 1
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Human-specifically rewired gene expression by HS lncRNAs in the anterior cingulate cortex (BA24).

(A) Genes expressed in the anterior cingulate cortex are enriched for HS lncRNAs’ target genes and neurodevelopment-related pathways. Squares, dots, and colors indicate HS lncRNAs, gene modules, and enriched KEGG pathways, respectively. (B) Comparison of modules and genes in humans (indicated by H) and macaques (indicated by M).

Author response image 1
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Distribution of per-base sequence distances for DBS size-matched random genomic windows in Ensembl-annotated promoter regions, calculated between modern humans and (A) chimpanzee, (B) Altai Neanderthal, (C) Denisovan, and (D) Vindija Neanderthal genomes.

Tables

Table 1
Genes with DBSs that have largest affinity values and mostly changed sequence distances (from modern humans to archaic humans and chimpanzees).
Target geneAnnotationBinding affinityMostly changed
IFNAR1That is, Interferon Alpha and Beta Receptor Subunit 1.794C, D
NFATC1A TF that induces gene transcription during immune responses.736C
NFATC1A TF that induces gene transcription during immune responses.491C, A, D
ANKLE2Diseases associated with ANKLE2 include microcephaly.527C, D
SEMA4DRegulating phosphatidylinositol 3-kinase signaling, neuron projection development, and phosphate metabolic process.495C, A, D
KIF21BEssential for neuronal morphology, synapse function, and learning and memory.471C
ALDH3B2An aldehyde dehydrogenase for alcohol metabolism.444C
NTSR1A brain and gastrointestinal peptide that mediates functions of neurotensin (e.g., hypotension, hyperglycemia, hypothermia, and antinociception).402C, A, D
MC5RA receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone.397C
THEGSpecifically expressed in the germ cells and involved in spermatogenesis.395C, D
HERC6In pathways including class I MHC-mediated antigen processing and presentation, and the innate immune system.369C, A, D
SLC2A11Facilitating glucose transporter.356C
NGEFPlaying a role in axon guidance regulating ephrin-induced growth cone collapse and dendritic spine morphogenesis.354C
SHC2Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons.345C, D
BAIAP3Regulating behavior and food intake by controlling calcium-stimulated exocytosis of neurotransmitters, serotonin, and hormones like Insulin.321C
SLURP1A marker of late differentiation of the skin.319C
MLPHInvolved in melanosome transport.307C
TAS1R3Responding to the umami taste stimulus and recognizing diverse natural and synthetic sweeteners.304C, D
SLC2A1A major glucose transporter in the mammalian blood–brain barrier.356C
CTD-3224I3.3An lncRNA is highly expressed in the cerebellum, lung, and testis.312C, A, D

  1. ‘C’, ‘A’, ‘D’, and ‘V’ indicate that the DBS has mostly changed sequence distances from modern humans to chimpanzees, Altai Neanderthals, Denisovans, and Vindija Neanderthals, respectively. NFATC1 is displayed in two rows because the DBSs of SNORA59B and TTTY8/TTTY8B have different affinity values.

Table 2
GO terms generated by different gene sets with large and small DBS distances from humans to chimpanzees and Altai Neanderthals.
Top 25% genes (sorted by DBS distance from humans to chimpanzees) in Supplementary file 1F, column Aterm_idadj_pBottom 25% genes (sorted by DBS distance from humans to chimpanzees) in Supplementary file 1F, column Aterm_idadj_p
BehaviorGO:00076108.26E−07Head developmentGO:00603221.96E−03
Head developmentGO:00603224.87E−05Forebrain developmentGO:00309002.26E−03
Brain developmentGO:00074202.69E−04Brain developmentGO:00074202.80E−03
Forebrain developmentGO:00309008.21E−03BehaviorGO:00076103.78E−03
Sensory organ developmentGO:00074231.07E−02Locomotory behaviorGO:00076261.75E−02
Learning or memoryGO:00076111.36E−02
Locomotory behaviorGO:00076261.63E−02
Sensory system developmentGO:00488801.93E−02
Sensory perception of soundGO:00076052.05E−02
Adaptive thermogenesisGO:19908453.49E−02
Top 25% genes (sorted by DBS distance from humans to Altai Neanderthals) in Supplementary file 1F, column Cterm_idadj_pBottom 25% genes (sorted by DBS distance from humans to Altai Neanderthals) in Supplementary file 1F, column Cterm_idadj_p
BehaviorGO:00076101.28E−09Brain developmentGO:00074201.34E−04
Head developmentGO:00603222.16E−05Sensory organ developmentGO:00074231.97E−04
Learning or memoryGO:00076112.66E−05Head developmentGO:00603223.98E−04
Brain developmentGO:00074204.15E−05Sensory organ morphogenesisGO:00905962.03E−03
Locomotory behaviorGO:00076267.74E−05BehaviorGO:00076109.69E−03
LearningGO:00076123.07E−04Locomotory behaviorGO:00076261.66E−02
Forebrain developmentGO:00309003.23E−04Sensory system developmentGO:00488804.72E−02
Sensory organ developmentGO:00074233.48E−04
Sensory system developmentGO:00488804.16E−04
Sensory organ morphogenesisGO:00905966.43E−03
Associative learningGO:00083066.43E−03
MemoryGO:00076131.18E−02
Social behaviorGO:00351761.37E−02
Sensory perception of soundGO:00076052.91E−02
Intersection of top 50% genes (sorted by DBS distance from humans to chimpanzees) and ASE genes in Supplementary file 1F, columns A and Fterm_idadj_pIntersection of bottom 50% genes (sorted by DBS distance from humans to chimpanzees) and ASE genes in Supplementary file 1F, columns A and Fterm_idadj_p
Cellular pigmentationGO:00330593.27E−05
PigmentationGO:00434733.94E−04
BehaviorGO:00076101.08E−03
Sensory system developmentGO:00488802.61E−03
LearningGO:00076123.69E−03
Learning or memoryGO:00076111.60E−02
Associative learningGO:00083061.62E−02
CognitionGO:00508902.06E−02
Sensory organ developmentGO:00074232.11E−02
Adaptive thermogenesisGO:19908453.16E−02
MemoryGO:00076134.85E−02
Intersection of top 50% genes (sorted by DBS distance from humans to Altai Neanderthals) and ASE genes in Supplementary file 1F, columns C and Fterm_idadj_pIntersection of bottom 50% genes (sorted by DBS distance from humans to Altai Neanderthals) and ASE genes in Supplementary file 1F, columns C and Fterm_idadj_p
BehaviorGO:00076103.88E−05PigmentationGO:00434737.11E−03
Sensory system developmentGO:00488804.09E−03Cellular pigmentationGO:00330591.10E−02
Sensory organ developmentGO:00074231.51E−02
Sensory perception of soundGO:00076053.95E−02
LearningGO:00076124.74E−02
Learning or memoryGO:00076114.77E−02

  1. The presence and absence of human evolution-related GO terms in the ORA results (Supplementary file 1G, H). Left: The top genes. Right: The bottom genes. Upper (black): Target genes. Bottom (blue): The intersections of target genes and genes with significant ASE (p-adj <0.01 and |LFC| >0.5). HS lncRNAs’ target genes are sorted by DBS distance from humans to chimpanzees and Altai Neanderthals.

Table 3
Genes with DBSs that are most polymorphic and have mostly changed sequence distances from humans to archaic humans and chimpanzees.
Target geneAnnotationSNP numberMostly changed
IFNAR1That is, Interferon Alpha and Beta Receptor Subunit 1.31C, D
DECR2The related pathways include metabolism and regulation of lipid metabolism.17C, A, D
DOK7Essential for neuromuscular synaptogenesis.17C, D
TAS1R3Responding to the umami taste stimulus and recognizing diverse natural and synthetic sweeteners.17C, D
NFATC1A TF that induces gene transcription during immune responses.16C, D
ST3GAL4Involved in protein glycosylation.15C, D
CAMK2BCalcium/calmodulin-dependent protein kinase important for dendritic spine and synapse formation and maintaining synaptic plasticity.13C, D
HLA-DQB1-AS1Highly expressed in EBV-transformed lymphocytes, lung, and spleen.13C, A, D, V
ANKLE2Diseases associated with ANKLE2 include microcephaly.12C, D
KRTAP1-3The KAP proteins form a matrix of keratin intermediate filaments that contribute to the structure of hair fibers.12C, D
INS, INS-IGF2Insulin decreases blood glucose concentration.11C, A, D
SHC2Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons.11C, D
FN3KRPDeglycating proteins to restore their function, important for modern humans adaptive to high glucose intake and functions in all tissues.10C, D
TFB1MThe encoded protein is part of the basal mitochondrial transcription complex and is necessary for mitochondrial gene expression.10C, A, D

  1. Some protein-coding genes that have (1) large DBS distances from humans to chimpanzees, (2) large DBS distances to Altai Neanderthals, Denisovans, or Vindija Neanderthals, and (3) dense SNPs. Letters C, A, D, and V indicate that DBS distance from humans to chimpanzees, Altai Neanderthals, Denisovans, and Vindija Neanderthals ≥0.037. Note that different HS lncRNAs’ DBSs in a gene may have somewhat different sequences, weighted Fst, and Tajima’s D.

Appendix 3—table 1
The enriched GO terms for the top 2000 and bottom 2000 genes with largest and smallest binding affinity.

Upper (black): Top 30 GO terms of the top 2000 genes (left) and the bottom 2000 genes (right). Lower (blue): Bottom 13 GO terms of the top 2000 genes (left) and 30 of bottom GO terms of the bottom 2000 genes (right).

GO terms (genes with strongest DBS)Term_idAdjusted_pGO terms (genes with weakest DBS)Term_idAdjusted_p
Small GTPase mediated signal transductionGO:00072648.55E−17Neuron projection developmentGO:00311753.79E−11
Neuron projection developmentGO:00311752.36E−16Cell morphogenesis involved in differentiationGO:00009045.36E−11
Cell projection morphogenesisGO:00488585.53E−16Cellular component morphogenesisGO:00329896.81E−11
Neuron projection morphogenesisGO:00488128.56E−16Regulation of plasma membrane bounded cell projection organizationGO:01200352.58E−10
Plasma membrane bounded cell projection morphogenesisGO:01200398.56E−16Plasma membrane bounded cell projection morphogenesisGO:01200393.44E−10
Cell junction organizationGO:00343301.96E−15Regulation of anatomical structure morphogenesisGO:00226034.34E−10
Cell part morphogenesisGO:00329905.24E−15Cell projection morphogenesisGO:00488584.88E−10
Synaptic signalingGO:00995361.38E−14Cell part morphogenesisGO:00329906.25E−10
Cellular component morphogenesisGO:00329893.76E−14Regulation of cell projection organizationGO:00313441.13E−09
Trans-synaptic signalingGO:00995371.88E−13Neuron projection morphogenesisGO:00488121.64E−09
Cell morphogenesis involved in differentiationGO:00009043.16E−13Actin filament-based processGO:00300291.65E−09
Regulation of small GTPase mediated signal transductionGO:00510564.03E−13Actin cytoskeleton organizationGO:00300361.99E−09
Chemical synaptic transmissionGO:00072684.18E−13Organophosphate metabolic processGO:00196372.05E−09
Anterograde trans-synaptic signalingGO:00989164.18E−13Cell morphogenesis involved in neuron differentiationGO:00486672.47E−09
Regulation of plasma membrane bounded cell projection organizationGO:01200351.72E−12Regulation of cellular component biogenesisGO:00440878.54E−09
Regulation of cell projection organizationGO:00313441.74E−12Regulation of neuron projection developmentGO:00109751.22E−08
Cell morphogenesis involved in neuron differentiationGO:00486673.83E−12Cell junction organizationGO:00343303.32E−08
Dendrite developmentGO:00163584.71E−11Organophosphate biosynthetic processGO:00904073.82E−08
Enzyme-linked receptor protein signaling pathwayGO:00071674.71E−11GrowthGO:00400073.85E−08
Cell surface receptor signaling pathway involved in cell–cell signalingGO:19051144.86E−11Developmental growthGO:00485895.54E−08
Actin filament-based processGO:00300297.42E−11Positive regulation of protein modification processGO:00314019.39E−08
Regulation of transmembrane transportGO:00347628.88E−11Regulation of cell morphogenesisGO:00226041.08E−07
Synapse organizationGO:00508081.07E−10Negative regulation of cellular component organizationGO:00511291.64E−07
Regulation of cellular component biogenesisGO:00440871.17E−10Lipid biosynthetic processGO:00086102.44E−07
Metal ion transportGO:00300014.76E−10Positive regulation of transportGO:00510503.52E−07
Ras protein signal transductionGO:00072655.80E−10Regulation of locomotionGO:00400124.21E−07
Regulation of ion transportGO:00432697.96E−10Organelle assemblyGO:00709254.42E−07
Modulation of chemical synaptic transmissionGO:00508048.08E−10Regulation of cell migrationGO:00303344.90E−07
Regulation of trans-synaptic signalingGO:00991778.80E−10Mitotic cell cycleGO:00002786.42E−07
Cation transmembrane transportGO:00986551.65E−09Synapse organizationGO:00508086.74E−07
Absent speechHP:00013441.54E−02Glycolipid metabolic processGO:00066643.80E−02
Abnormal aggressive, impulsive, or violent behaviorHP:00069191.54E−02Carboxylic acid catabolic processGO:00463953.80E−02
Autistic behaviorHP:00007291.54E−02Regulation of epithelial cell proliferationGO:00506783.83E−02
Absent toeHP:00107601.89E−02Response to radiationGO:00093143.85E−02
Abnormality of calvarial morphologyHP:00026481.89E−02Protein methylationGO:00064793.86E−02
Aplasia/hypoplasia of toeHP:00019911.89E−02Protein alkylationGO:00082133.86E−02
Tall statureHP:00000981.89E−02Golgi organizationGO:00070303.88E−02
Short philtrumHP:00003221.89E−02Membrane depolarizationGO:00518993.97E−02
Motor stereotypyHP:00007333.37E−02Skeletal system morphogenesisGO:00487053.98E−02
Slender fingerHP:00012383.37E−02Positive chemotaxisGO:00509183.98E−02
Asymmetric growthHP:01005553.37E−02Development of primary sexual characteristicsGO:00451373.98E−02
Abnormal upper limb bone morphologyHP:00400703.37E−02Metaphase/anaphase transition of cell cycleGO:00447843.98E−02
Long fingersHP:01008074.09E−02Non-motile cilium assemblyGO:19055153.98E−02
Muscle cell differentiationGO:00426924.55E−02
Cell activation involved in immune responseGO:00022634.73E−02
Regulation of exocytosisGO:00171574.74E−02
Negative regulation of chromosome organizationGO:20012514.76E−02
ADP metabolic processGO:00460314.76E−02
Cytoskeleton-dependent cytokinesisGO:00616404.76E−02
Regulation of canonical Wnt signaling pathwayGO:00608284.77E−02
Olefinic compound metabolic processGO:01202544.77E−02
DNA geometric changeGO:00323924.77E−02
Gonad developmentGO:00084064.77E−02
Reproductive system developmentGO:00614584.77E−02
Vasculature developmentGO:00019444.77E−02
Response to insulinGO:00328684.79E−02
Ribonucleotide biosynthetic processGO:00092604.79E−02
Organic acid biosynthetic processGO:00160534.82E−02
Vacuole organizationGO:00070334.84E−02
Import across plasma membraneGO:00987394.95E−02
Appendix 3—table 2
Enriched GO terms of different sets of genes 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. The intersections of genes sorted by DBS distance from humans to chimpanzees and to Altai Neanderthals, respectively, and genes showing significant ASE (adj-p <0.01 and |LFC| >0.5).

Intersection of top 50% of genes (sorted by DBS distance from humans to chimpanzees) and ASE genes (adj-p <0.01)term_IDadj_pIntersection of bottom 50% of genes (sorted by DBS distance from humans to chimpanzees) and ASE genes (adj-p <0.01)term_IDadj_p
Cellular pigmentationGO:00330592.41E−06Brain developmentGO:00074207.80E−03
BehaviorGO:00076105.78E−05Forebrain developmentGO:00309004.34E−02
PigmentationGO:00434737.68E−05
LearningGO:00076123.60E−04
Associative learningGO:00083062.08E−03
Adaptive thermogenesisGO:19908452.28E−03
Sensory system developmentGO:00488803.19E−03
Cold-induced thermogenesisGO:01061063.78E−03
Digestive system developmentGO:00551233.94E−03
Glucose metabolic processGO:00060063.97E−03
Learning or memoryGO:00076114.69E−03
CognitionGO:00508906.32E−03
Regulation of cold-induced thermogenesisGO:01201616.33E−03
MemoryGO:00076134.42E−02
Alcohol metabolic processGO:00060664.82E−02
Intersection of top 50% of genes (sorted by DBS distance from humans to Altai Neanderthals) and ASE genes (adj-p <0.01)term_IDadj_pIntersection of bottom 50% of genes (sorted by DBS distance from humans to Altai Neanderthals) and ASE genes (adj-p <0.01)term_IDadj_p
BehaviorGO:00076102.52E−07PigmentationGO:00434734.39E−04
Glucose metabolic processGO:00060069.29E−04Cellular pigmentationGO:00330592.74E−03
Sensory system developmentGO:00488801.05E−03Brain developmentGO:00074204.96E−02
LearningGO:00076121.77E−03
Learning or memoryGO:00076113.62E−03
CognitionGO:00508904.42E−03
Associative learningGO:00083066.95E−03
Digestive system developmentGO:00551238.54E−03
Cold-induced thermogenesisGO:01061061.43E−02
Adaptive thermogenesisGO:19908451.50E−02
Brain developmentGO:00074201.85E−02
Forebrain developmentGO:00309002.04E−02
Regulation of cold-induced thermogenesisGO:01201612.28E−02
Alcohol metabolic processGO:00060662.38E−02
MemoryGO:00076132.72E−02
Visual behaviorGO:00076324.57E−02
Appendix 3—table 3
Numbers of favored and hitchhiking mutations in different classes of DBSs.
Hitchhiking SNPsStrong oldStrong youngStrong othersWeak oldWeak youngWeak others
3/15,68511/163,00778/170,38910/180,50544/47,25157/168,692
Favored SNPsStrong oldStrong youngStrong othersWeak oldWeak youngWeak others
0/10,2161/16,0404/92,1530/26,5325/31,2422/108,014
Appendix 6—table 1
The 14 SNPs have high DAF in YRI and are eQTLs exclusively in the GTEx tissue Thyroid.
SNP IDCEU-frequencyCHB-frequencyYRI-frequency
rs755082160.010.050.1
rs1140869930.010.050.1
rs2011879710.0100.1
rs73677017000.14
rs11944829000.14
rs114884549000.15
rs77133472000.15
rs115688283000.17
rs113131895000.17
rs14252298100.020.19
rs112731299000.2
rs45658030.0100.24
rs46047790.0100.24
rs766124330.020.190.24
Author response table 1
Sensitivity analysis of GO-term enrichment across different DBS sequence distance cutoffs.

The table shows the numbers of target genes identified and the false discovery rates (FDR) for the enrichment of three selected GO terms at four different distance cutoffs. Note that, unlike in the old Figure 2, the results for chimpanzees and Altai Neanderthals are not directly comparable here, as the numbers of target genes used for the enrichment analysis differ between them at each cutoff.

Cutoff = 0.03Cutoff = 0.034Cutoff = 0.04Cutoff = 0.05
ChimpAltaiChimpAltaiChimpAltaiChimpAltai
Target gene with distance > cutoff7087181742481256378910363223745
Behavior (FDR)7.06E-058.56E-037.10E-071.32E-062.31E-054.65E-055.17E-050.00741
Neuron projection development (FDR)2.91E-051.77 E -021.41 E -089.91E-054.52E-070.018874.22E-05NS
Synaptic signaling (FDR)1.86E-084.99E-034.60E-072.34E-054.32 E -076.31 E -059.11E-070.001891

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/89001/elife-89001-mdarchecklist1-v1.pdf
Supplementary file 1

All supplementary results from this study (including 18 tables).

https://cdn.elifesciences.org/articles/89001/elife-89001-supp1-v1.xlsx

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  1. Jie Lin
  2. Yujian Wen
  3. Ji Tang
  4. Xuecong Zhang
  5. Huanlin Zhang
  6. Hao Zhu
(2026)
Human-specific lncRNAs contributed critically to human evolution by distinctly regulating gene expression
eLife 12:RP89001.
https://doi.org/10.7554/eLife.89001.6