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Abstract
The divergence rate between the alignable genomes of humans and chimpanzees is as little as 1.23%. Their phenotypical difference was hypothesized to be accounted for by gene regulation. We construct the cis-regulatory element frequency (CREF) matrix to represent the proximal regulatory sequences for each species. Each CREF matrix is further decomposed into dual eigen-modules. By comparing the CREF modules of four existing hominid species, we examine their quantitative and qualitative changes along evolution. We identified two saltations: one between the 4th and 5th, the other between the 9th and 10th eigen-levels. The cognition and intelligence unique to humans are thus found from the saltations at the molecular level. They include long-term memory, cochlea/inner ear morphogenesis that enables the development of human language/music, social behavior that allows us to live together peacefully and to work collaboratively, and visual/observational/associative learning. Moreover, we found exploratory behavior crucial for humans’ creativity, the GABA-B receptor activation that protects our neurons, and serotonin biosynthesis/signaling that regulates our happiness. We observed a remarkable increase in the number of motifs present on Alu elements on the 4th/9th motif-eigenvectors. The cognition and intelligence unique to humans can, by and large, be identified using only the CREF profiles without any a priori. Although gradual evolution might be the only mode in the mutations of protein sequences, the evolution of gene regulation has both gradual and saltational modes, which could be explained by the framework of CREF eigen-modules.
Keywords
Alu element
/
gene regulation
/
human intelligence
/
saltation
/
serotonin
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Xiaojie Li, Jianhui Shi, Lei M. Li.
The human intelligence evolved from proximal cis-regulatory saltations.
Quant. Biol., 2025, 13(2): e88 DOI:10.1002/qub2.88
| [1] |
King MC , Wilson AC . Evolution at two levels in humans and chimpanzees. Science. 1975; 188 (4184): 107- 16.
|
| [2] |
Cao J , Luo Z , Cheng Q , Xu Q , Zhang Y , Wang F , et al. Three-dimensional regulation of transcription. Protein Cell. 2015; 6 (4): 241- 53.
|
| [3] |
Lee TI , Young RA . Transcriptional regulation and its misregulation in disease. Cell. 2013; 152 (6): 1237- 51.
|
| [4] |
Mitsis T , Efthimiadou A , Bacopoulou F , Vlachakis D , Chrousos GP , Eliopoulos E . Transcription factors and evolution: an integral part of gene expression (Review). World Academy of Sciences Journal. 2020; 2 (1): 3- 8.
|
| [5] |
Wray GA . The evolutionary significance of cis-regulatory mutations. Nat Rev Genet. 2007; 8 (3): 206- 16.
|
| [6] |
Ewens WJ , Grant GR . Statistical methods in bioinformatics: an introduction. 2nd ed. New York: Springer; 2005. p. 597. (Statistics for biology and health).
|
| [7] |
Ewens WJ . Mathematical population genetics. 1: theoretical introduction. 2. ed. New York: Springer; 2004. p. 417. (Interdisciplinary applied mathematics Mathematical biology).
|
| [8] |
Horton CA , Alexandari AM , Hayes MGB , Marklund E , Schaepe JM , Aditham AK , et al. Short tandem repeats bind transcription factors to tune eukaryotic gene expression. Science. 2023; 381 (6664): eadd1250.
|
| [9] |
Wright SE , Todd PK . Native functions of short tandem repeats. Elife. 2023; 12: e84043.
|
| [10] |
Polak P , Domany E . Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genom. 2006; 7: 133.
|
| [11] |
Li L , Zhang S , Li LM . Dual eigen-modules of cis-element regulation profiles and selection of cognition-language eigen-direction along evolution in Hominidae. Mol Biol Evol. 2020; 37 (6): 1679- 93.
|
| [12] |
Kumar S , Stecher G , Suleski M , Hedges SB . TimeTree: a resource for timelines, timetrees, and divergence times. Mol Biol Evol. 2017; 34 (7): 1812- 9.
|
| [13] |
Doniger SW , Fay JC . Frequent gain and loss of functional transcription factor binding sites. PLoS Comput Biol. 2007; 3 (5): e99.
|
| [14] |
Matys V . TRANSFAC (R) and its module TRANSCompel (R): transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2006; 34 (90001): D108- 10.
|
| [15] |
Kel AE , Gößling E , Reuter I , Cheremushkin E , Kel-Margoulis OV , Wingender E . MATCHTM: a tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 2003; 31 (13): 3576- 9.
|
| [16] |
Zhang C , Xuan Z , Otto S , Hover JR , McCorkle SR , Mandel G , et al. A clustering property of highly-degenerate transcription factor binding sites in the mammalian genome. Nucleic Acids Res. 2006; 34 (8): 2238- 46.
|
| [17] |
Paixão T , Azevedo RBR . Redundancy and the evolution of cis-regulatory element multiplicity. PLoS Comput Biol. 2010; 6 (7): e1000848.
|
| [18] |
Xu H , Sepúlveda LA , Figard L , Sokac AM , Golding I . Combining protein and mRNA quantification to decipher transcriptional regulation. Nat Methods. 2015; 12 (8): 739- 42.
|
| [19] |
Doughty BR , Hinks MM , Schaepe JM , Marinov GK , Thurm AR , Rios-Martinez C , et al. Single-molecule chromatin configurations link transcription factor binding to expression in human cells. 2024. Preprint at bioRxiv: 2024.02.02.578660.
|
| [20] |
Feng Y , Zhang S , Li L , Li LM . The cis-trans binding strength defined by motif frequencies facilitates statistical inference of transcriptional regulation. BMC Bioinf. 2019; 20 (7): 201.
|
| [21] |
Tang W , Mun S , Joshi A , Han K , Liang P . Mobile elements contribute to the uniqueness of human genome with 15,000 human-specific insertions and 14 Mbp sequence increase. DNA Res. 2018; 25 (5): 521- 33.
|
| [22] |
Lin Z , Chen M , Ma Y . The augmented Lagrange multiplier method for exact recovery of corrupted low-rank matrices. J Struct Biol. 2013; 181 (2): 116- 27.
|
| [23] |
Stewart GW , Sun Jguang . Matrix perturbation theory. Boston: Academic Press; 1990. (Computer science and scientific computing). p. 365.
|
| [24] |
Li L . The evolution of transcription regulation in Hominidae from the perspective of cis-element frequency[Ph.D. Thesis]. University of Chinese Academy of Sciences; 2021.
|
| [25] |
Eigenvalue perturbation. In: Wikipedia[Internet]. 2024 [cited 2024 Aug 22].
|
| [26] |
Cheng C , Fabrizio P , Ge H , Wei M , Longo VD , Li LM . Significant and systematic expression differentiation in long-lived yeast strains. PLoS One. 2007; 2 (10): e1095.
|
| [27] |
Morris WE , Brown CR , David Hume . In: Zalta EN, Nodelman U, editors. The stanford encyclopedia of philosophy[Internet]. Winter 2023. Metaphysics Research Lab, Stanford University; 2023. [cited 2024 Jun 29].
|
| [28] |
Gruber MJ , Ranganath C . How curiosity enhances hippocampus-dependent memory: the prediction, appraisal, curiosity, and exploration (PACE) framework. Trends Cognit Sci. 2019; 23 (12): 1014- 25.
|
| [29] |
Serotonin. In: Wikipedia[internet]. 2024 [cited 2024 Jun 25].
|
| [30] |
Flitton M , Rielly N , Warman R , Warden D , Smith AD , Macdonald IA , et al. Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline. Neurobiol Aging. 2019; 78: 64- 73.
|
| [31] |
Zhang B , Wang Q , Miao T , Yu B , Yuan P , Kong J , et al. Whether Alzheimer's diseases related genes also differently express in the hippocampus of Ts65Dn mice? Int J Clin Exp Pathol. 2015; 8 (4): 4120- 5.
|
| [32] |
Collins SM , Belagodu AP , Reed SL , Galvez R . SHANK1 is differentially expressed during development in CA1 hippocampal neurons and astrocytes. Dev Neurobiol. 2018; 78 (4): 363- 73.
|
| [33] |
Södersten E , Lilja T , Hermanson O . The novel BTB/POZ and zinc finger factor Zbtb45 is essential for proper glial differentiation of neural and oligodendrocyte progenitor cells. Cell Cycle. 2010; 9 (24): 4866- 75.
|
| [34] |
Plitt MH , Kaganovsky K , Südhof TC , Giocomo LM . Hippocampal place code plasticity in CA1 requires postsynaptic membrane fusion. 2023. Preprint at bioRxiv: 2023.11.20.567978.
|
| [35] |
Roy ER , Chiu G , Li S , Propson NE , Kanchi R , Wang B , et al. Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques. Immunity. 2022; 55 (5): 879- 94.e6.
|
| [36] |
Ma Z , Zeng Y , Wang M , Liu W , Zhou J , Wu C , et al. N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development. EMBO J. 2023; 42 (22): e113383.
|
| [37] |
Woodward KJ , Stampalia J , Vanyai H , Rijhumal H , Potts K , Taylor F , et al. Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance. Mol Genet Genomic Med. 2019; 7 (2): e00507.
|
| [38] |
Kong X , Shu X , Wang J , Liu D , Ni Y , Zhao W , et al. Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development. Development. 2022; 149 (24): dev201286.
|
| [39] |
Neyazi B , Tanrikulu L , Wilkens L , Hartmann C , Stein KP , Dumitru CA , et al. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 expression in brain arteriovenous malformations and its association with brain arteriovenous malformation size. World Neurosurg. 2017; 102: 79- 84.
|
| [40] |
Li M , Yue W . VRK2, a candidate gene for psychiatric and neurological disorders. Mol Neuropsychiatry. 2018; 4 (3): 119- 33.
|
| [41] |
Yoshihara T , Satake H , Nishie T , Okino N , Hatta T , Otani H , et al. Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice. PLoS Genet. 2018; 14 (8): e1007545.
|
| [42] |
Alberini CM . Transcription factors in long-term memory and synaptic plasticity. Physiol Rev. 2009; 89 (1): 121- 45.
|
| [43] |
Okamoto Sichi , Sherman K , Bai G , Lipton SA . Effect of the ubiquitous transcription factors, SP1 and MAZ, on NMDA receptor subunit type 1(NR1) expression during neuronal differentiation. Brain Res Mol Brain Res. 2002; 107 (2): 89- 96.
|
| [44] |
Alsiö JM , Tarchini B , Cayouette M , Livesey FJ . Ikaros promotes early-born neuronal fates in the cerebral cortex. Proc Natl Acad Sci USA. 2013; 110 (8): E716.
|
| [45] |
Agoston DV , Szemes M , Dobi A , Palkovits M , Georgopoulos K , Gyorgy A , et al. Ikaros is expressed in developing striatal neurons and involved in enkephalinergic differentiation. J Neurochem. 2007; 102 (6): 1805- 16.
|
| [46] |
Sakai H , Fujii Y , Kuwayama N , Kawaji K , Gotoh Y , Kishi Y . Plag1 regulates neuronal gene expression and neuronal differentiation of neocortical neural progenitor cells. Gene Cell. 2019; 24 (10): 650- 66.
|
| [47] |
Qin S , Zhang CL . Role of Kruppel-like factor 4 in neurogenesis and radial neuronal migration in the developing cerebral cortex. Mol Cell Biol. 2012; 32 (21): 4297- 305.
|
| [48] |
Qin S , Liu M , Niu W , Zhang CL . Dysregulation of Kruppel-like factor 4 during brain development leads to hydrocephalus in mice. Proc Natl Acad Sci USA. 2011; 108 (52): 21117- 21.
|
| [49] |
Topilko P , Schneider-Maunoury S , Levi G , Baron-Van Evercooren A , Chennoufi AB , Seitanidou T , et al. Krox-20 controls myelination in the peripheral nervous system. Nature. 1994; 371 (6500): 796- 9.
|
| [50] |
Cubelos B , Sebastián-Serrano A , Beccari L , Calcagnotto ME , Cisneros E , Kim S , et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron. 2010; 66 (4): 523- 35.
|
| [51] |
Yu WM , Appler JM , Kim YH , Nishitani AM , Holt JR , Goodrich LV . A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing. Elife. 2013; 2: e01341.
|
| [52] |
Zhang T , Xu J , Maire P , Xu PX . Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium. PLoS Genet. 2017; 13 (9): e1006967.
|
| [53] |
Zuber ME , Gestri G , Viczian AS , Barsacchi G , Harris WA . Specification of the vertebrate eye by a network of eye field transcription factors. Development. 2003; 130 (21): 5155- 67.
|
| [54] |
Li LM , Li M , Li L . Cis-regulatory element frequency modules and their phase transition across Hominidae. In: Lu HHS, Schölkopf B, Wells MT, Zhao H, editors. Handbook of statistical bioinformatics[Internet]. Berlin: Springer; 2022. p. 371- 95. [cited 2024 Jun 18].
|
| [55] |
Harris RA , Raveendran M , Worley KC , Rogers J . Unusual sequence characteristics of human chromosome 19 are conserved across 11 nonhuman primates. BMC Evol Biol. 2020; 20 (1): 33.
|
| [56] |
Peng Y , Bjelde A , Aceituno PV , Mittermaier FX , Planert H , Grosser S , et al. Directed and acyclic synaptic connectivity in the human layer 2-3 cortical microcircuit. Science. 2024; 384 (6693): 338- 43.
|
| [57] |
Bliskunova T , Genis-Mendoza AD , Martínez-Magaña JJ , Vega-Sevey JG , Jiménez-Genchi J , Roche A , et al. Association of MGAT4C with major neurocognitive disorder in the Mexican population. Gene. 2021; 778: 145484.
|
| [58] |
Preston M , Gong X , Su W , Matsumoto SG , Banine F , Winkler C , et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol. 2013; 73 (2): 266- 80.
|
| [59] |
Tu H , Xu C , Zhang W , Liu Q , Rondard P , Pin JP , et al. GABAB receptor activation protects neurons from apoptosis via IGF-1 receptor transactivation. J Neurosci. 2010; 30 (2): 749- 59.
|
| [60] |
Kingman JFC . Origins of the coalescent 1974-1982. Genetics. 2000; 156: 1461- 3.
|
| [61] |
Ao P . Laws in Darwinian evolutionary theory. Phys Life Rev. 2005; 2 (2): 117- 56.
|
| [62] |
Kimura M . The neutral theory of molecular evolution. Cambridge: Cambridge University Press; 1983.
|
| [63] |
Kramers HA , Wannier GH . Statistics of the two-dimensional ferromagnet Part II. Phys Rev. 1941; 60 (3): 263- 76.
|
| [64] |
Onsager L . Crystal statistics I. A two-dimensional model with an order-disorder transition. Phys Rev. 1944; 65 (3-4): 117- 49.
|
| [65] |
Kaufman B , Onsager L . Crystal statistics. III. Short-range order in a binary ising lattice. Phys Rev. 1949; 76 (8): 1244- 52.
|
| [66] |
Yang CN . The spontaneous magnetization of a two-dimensional ising model. Phys Rev. 1952; 85 (5): 808- 16.
|
| [67] |
Montroll EW , Potts RB , Ward JC . Correlations and spontaneous magnetization of the two-dimensional ising model. J Math Phys. 1963; 4 (2): 308- 22.
|
| [68] |
Deift P , Its A , Krasovsky I . Toeplitz matrices and toeplitz determinants under the impetus of the ising model: some history and some recent results. Commun Pure Appl Math. 2013; 66 (9): 1360- 438.
|
| [69] |
Kac M , Thompson CJ . On the mathematical mechanism of phase transition. Proc Natl Acad Sci USA. 1966; 55 (4): 676- 83.
|
| [70] |
Crick FH . On protein synthesis. Symp Soc Exp Biol. 1958; 12: 138- 63.
|
| [71] |
Hegel GWF . In: Di Giovanni G, editor. Georg Wilhelm friedrich Hegel: the science of logic[Internet]. Cambridge: Cambridge University Press; 2010. [cited 2024 Jun 18]. (Cambridge Hegel Translations).
|
| [72] |
Cheng C , Fabrizio P , Ge H , Wei M , Longo VD , Li LM . Significant and systematic expression differentiation in long-lived yeast strains. PLoS One. 2007; 2 (10): e1095.
|
| [73] |
Ashburner M , Ball CA , Blake JA , Botstein D , Butler H , Cherry JM , et al. Gene Ontology: tool for the unification of biology. Nat Genet. 2000; 25 (1): 25- 9.
|
| [74] |
Aleksander SA , Aleksander SA , Balhoff J , Carbon S , Cherry JM , Drabkin HJ , et al. The gene Ontology knowledgebase in 2023. Genetics. 2023; 224 (1): iyad031.
|
| [75] |
Kanehisa M , Furumichi M , Tanabe M , Sato Y , Morishima K . KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017; 45 (D1): D353- 61.
|
| [76] |
Kanehisa M , Furumichi M , Sato Y , Kawashima M , Ishiguro-Watanabe M . KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023; 51 (D1): D587- 92.
|
| [77] |
Milacic M , Beavers D , Conley P , Gong C , Gillespie M , Griss J , et al. The reactome pathway knowledgebase 2024. Nucleic Acids Res. 2024; 52 (D1): D672- 8.
|
| [78] |
Bao W , Kojima KK , Kohany O . Repbase Update, a database of repetitive elements in eukaryotic genomes. Mobile DNA. 2015; 6 (1): 11.
|
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