Abstract—
It is thought that changes in mechanisms of gene regulation have played the critical role in human evolution, rather than changes in protein-coding sequences. Recent studies have discovered a special class of genome elements, human accelerated regions (HARs). These elements are conserved non-coding DNA sequences of mammals that have been accumulating human-specific mutations throughout the evolution. Starting from their discovery, the actual role of HARs in human evolution has remained unclear, since they are almost exclusively represented by non-coding sequences with no annotations. It is now known that HAR elements are enriched with binding motifs of transcription factors and histone markers of active chromatin. Recent investigations using functional genomics, computational methods, and genetic analysis have demonstrated that many HARs participate in the genetic regulation of development and have made a major contribution to the evolution of the human brain—in particular, the enlargement of the cerebral cortex. Furthermore, there is much evidence that there is relationship between the polymorphisms of HAR sequences and development of various neurological diseases, such as autism spectrum disorders, schizophrenia, and Huntington’s disease. Such functional methods of analysis as massively parallel reporter assay and screenings using the CRISPR system significantly increase the amount of described regulatory elements specific for human beings. Further investigation of HARs and other evolutionary dynamic genome regions might clarify sophisticated evolutionary changes underlying the unique cytoarchitecture and cognitive abilities of the human brain. Here, we have elucidated the approaches to HAR identification in the genome and their role in regulation of gene activity and effect on the evolution of the human brain and reviewed certain pathological effects of mutations in HAR sequences.
Similar content being viewed by others
REFERENCES
Aboitiz, F. and García, R.V., The evolutionary origin of the language areas in the human brain. A neuroanatomical perspective, Brain Res. Brain Res. Rev., 1997, vol. 25, p. 381. https://doi.org/10.1016/s0165-0173(97)00053-2
Alarcón, M., Abrahams, B.S., Stone, J.L., Duvall, J.A., Perederiy, J.V., Bomar, J.M., Sebat, J., Wigler, M., Martin, C.L., Ledbetter, D.H., Nelson, S.F., Can-tor, R.M., and Geschwind, D.H., Linkage, association, and gene-expression analyses identify CNTNAP2 as an a-utism-susceptibility gene, Am. J. Hum. Genet., 2008, vol. 82, p. 150. https://doi.org/10.1016/j.ajhg.2007.09.005
Allen, N.J., Bennett, M.L., Foo, L.C., Wang, G.X., Chakraborty, C., Smith, S.J., and Barres, B.A., Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors, Nature, 2012, vol. 486, p. 410. https://doi.org/10.1038/nature11059
Ashuach, T., Fischer, D.S., Kreimer, A., Ahituv, N., Theis, F.J., and Yosef, N., MPRAnalyze: statistical framework for massively parallel reporter assays, Genome. Biol., 2019, vol. 20, p. 183. https://doi.org/10.1186/s13059-019-1787-z
Atkinson, E.G., Audesse, A.J., Palacios, J.A., Bobo, D.M., Webb, A.E., Ramachandran, S., and Henn, B.M., No evidence for recent selection at FOXP2 among diverse human populations, Cell, 2018, vol. 174, p. 1424. https://doi.org/10.1016/j.cell.2018.06.048
Bailey, J.A., Gu, Z., Clark, R.A., Reinert, K., Samonte, R.V., Schwartz, S., Adams, M.D., Myers, E.W., Li, P.W., and Eichler, E.E., Recent segmental duplications in the human genome, Science, 2002, vol. 297, p. 1003. https://doi.org/10.1126/science.1072047
Barnby, G., Abbott, A., Sykes, N., Morris, A., Weeks, D.E., Mott, R., Lamb, J., Bailey, A.J., Monaco, A.P., and International Molecular Genetics Study of Autism Consortium, Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT, Am. J. Hum. Genet., 2005, vol. 76, p. 950. https://doi.org/10.1086/430454
Betizeau, M., Cortay, V., Patti, D., Pfister, S., Gautier, E., Bellemin-Ménard, A., Afanassieff, M., Huissoud, C., Douglas, R.J., Kennedy, H., and Dehay, C., Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate, Neuron, 2013, vol. 80, p. 442. https://doi.org/10.1016/j.neuron.2013.09.032
Bhattacharyya, U., Deshpande, S.N., Bhatia, T., and Thelma, B.K., Revisiting schizophrenia from an evolutionary perspective: an association study of recent evolutionary markers and schizophrenia, Schizophr. Bull., 2021, vol. 47, p. 827. https://doi.org/10.1093/schbul/sbaa179
Bird, C.P., Stranger, B.E., Liu, M., Thomas, D.J., Ingle, C.E., Beazley, C., Miller, W., Hurles, M.E., and Dermitzakis, E.T., Fast-evolving noncoding sequences in the human genome, Genome Biol., 2007, vol. 8, p. R118. https://doi.org/10.1186/gb-2007-8-6-r118
Boyd, J.L., Skove, S.L., Rouanet, J.P., Pilaz, L.J., Bepler, T., Gordân, R., Wray, G.A., and Silver, D.L., Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex, Curr. B-iol., 2015, vol. 25, p. 772. https://doi.org/10.1016/j.cub.2015.01.041
Bruce, H.A. and Margolis, R.L., FOXP2: novel exons, splice variants, and CAG repeat length stability, Hum. G-enet., 2002, vol. 111, p. 136. https://doi.org/10.1007/s00439-002-0768-5
Bush, E.C. and Lahn, B.T., A genome-wide screen for noncoding elements important in primate evolution, BMC Evol. Biol., 2008, vol. 8, p. 17. https://doi.org/10.1186/1471-2148-8-17
Caporale, A.L., Gonda, C.M., and Franchini, L.F., Transcriptional enhancers in the FOXP2 locus underwent accelerated evolution in the human lineage, Mol. Biol. Evol., 2019, vol. 36, p. 2432. https://doi.org/10.1093/molbev/msz173
Capra, J.A., Erwin, G.D., McKinsey, G., Rubenstein, J.L., and Pollard, K.S., Many human accelerated regions are developmental enhancers, Philos. Trans. R. Soc. London, B, 2013, vol. 368, p. 20130025. https://doi.org/10.1098/rstb.2013.0025
Chan, Y.F., Marks, M.E., Jones, F.C., Villarreal, G., Shapiro, M.D., Brady, S.D., Southwick, A.M., Absher, D.M., Grimwood, J., Schmutz, J., Myers, R.M., Petrov, D., Jónsson, B., Schluter, D., Bell, M.A., et al., Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer, Science, 2010, vol. 327, p. 302. https://doi.org/10.1126/science.1182213
Charrier, C., Joshi, K., Coutinho-Budd, J., Kim, J.E., Lambert, N., de Marchena, J., Jin, W.L., Vanderhaeghen, P., Ghosh, A., Sassa, T., and Polleux, F., Inhibition of SR-GAP2 function by its human-specific paralogs induces neoteny during spine maturation, Cell, 2012, vol. 149, p. 923. https://doi.org/10.1016/j.cell.2012.03.034
Consortium, Chimpanzee Sequencing and Analysis. Initial sequence of the chimpanzee genome and comparison with the human genome, Nature. 2005, vol. 437, p. 69. https://doi.org/10.1038/nature04072
Cooper, K.L., Sears, K.E., Uygur, A., Maier, J., Baczkowski, K.S., Brosnahan, M., Antczak, D., Skidmore, J.A., and Tabin, C.J., Patterning and post-patterning modes of evolutionary digit loss in mammals, Nature, 2014, vol. 511, p. 41.https://doi.org/10.1038/nature13496
Cretekos, C.J., Wang, Y., Green, E.D., Martin, J.F., Rasweiler, J.J., and Behringer, R.R., Regulatory divergence modifies limb length between mammals, Genes Dev., 2008, vol. 22, p. 141. https://doi.org/10.1101/gad.1620408
Cubelos, B., Briz, C.G., Esteban-Ortega, G.M., and Nieto, M., Cux1 and Cux2 selectively target basal and apical dendritic compartments of layer II−III cortical neurons, Dev. Neurobiol., 2015, vol. 75, p. 163. https://doi.org/10.1002/dneu.22215
Dehay, C., Kennedy, H., and Kosik, K.S., The outer subventricular zone and primate-specific cortical complexification, Neuron, 2015, vol. 85, p. 683. https://doi.org/10.1016/j.neuron.2014.12.060
Dennis, M.Y., Nuttle, X., Sudmant, P.H., Antonacci, F., Graves, T.A., Nefedov, M., Rosenfeld, J.A., Sajjadian, S., Malig, M., Kotkiewicz, H., Curry, C.J., Shafer, S., Shaf-fer, L.G., de Jong, P.J., Wilson, R.K., and Eichler, E.E., Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication, Cell, 2012, vol. 149, p. 912. https://doi.org/10.1016/j.cell.2012.03.033
Dermitzakis, E.T. and Clark, A.G., Evolution of transcription factor binding sites in Mammalian gene regulatory regions: conservation and turnover, Mol. Biol. Evol., 2002, vol. 19, p. 1114. https://doi.org/10.1093/oxfordjournals.molbev.a004169
Doan, R.N., Bae, B.I., Cubelos, B., Chang, C., Hossain, A.A., Al-Saad, S., Mukaddes, N.M., Oner, O., Al-Saffar, M., Balkhy, S., Gascon, G.G., Nieto, M., Walsh, C.A., and Homozygosity Mapping Consortium for Autism, Mutations in human accelerated regions disrupt cognition and social behavior, Cell, 2016, p. 341. https://doi.org/10.1016/j.cell.2016.08.071
Doggett, N.A., Xie, G., Meincke, L.J., Sutherland, R.D., Mundt, M.O., Berbari, N.S., Davy, B.E., Robinson, M.L., Rudd, M.K., Weber, J.L., Stallings, R.L., and Han, C., A 360-kb interchromosomal duplication of the human HY-DIN locus, Genomics, 2006, vol. 88, p. 762. https://doi.org/10.1016/j.ygeno.2006.07.012
Dorschner, M.O., Hawrylycz, M., Humbert, R., Wallace, J.C., Shafer, A., Kawamoto, J., Mack, J., Hall, R., Goldy, J., Sabo, P.J., Kohli, A., Li, Q., McArthur, M., and Stamatoyannopoulos, J.A., High-throughput localization of functional elements by quantitative chromatin profiling, Nat. Methods, 2004, vol. 1, p. 219. https://doi.org/10.1038/nmeth721
Enard, W., Przeworski, M., Fisher, S.E., Lai, C.S., Wiebe, V., Kitano, T., Monaco, A.P., and Pääbo, S., Molecular evolution of FOXP2, a gene involved in speech and language, Nature, 2002, vol. 418, p. 869. https://doi.org/10.1038/nature01025
Erady, C., Amin, K., Onilogbo, T.O.A.E., Tomasik, J., Jukes-Jones, R., Umrania, Y., Bahn, S., and Prabakaran, S., Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder, Mol. Psychiatry, 2021, vol. 27, p. 1455. https://doi.org/10.1038/s41380-021-01405-6
Felsenstein, J. and Churchill, G.A., A Hidden Markov Model approach to variation among sites in rate of evolution, Mol. Biol. Evol., 1996, vol. 13, p. 93. https://doi.org/10.1093/oxfordjournals.molbev.a025575
Feuk, L., Kalervo, A., Lipsanen-Nyman, M., Skaug, J., Nakabayashi, K., Finucane, B., Hartung, D., Innes, M., Kerem, B., Nowaczyk, M.J., Rivlin, J., Roberts, W., Senman, L., Summers, A., Szatmari, P., et al., Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia, Am. J. Hum. Genet., 2006, vol. 79, p. 965. https://doi.org/10.1086/508902
Fiddes, I.T., Lodewijk, G.A., Mooring, M., Bosworth, C.M., Ewing, A.D., Mantalas, G.L., Novak, A.M., van den Bout, A., Bishara, A., Rosenkrantz, J.L., Lorig-Roach, R., Field, A.R., Haeussler, M., Russo, L., Bhaduri, A., et al., Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis, Cell, 2018, vol. 173, p. 1356. https://doi.org/10.1016/j.cell.2018.03.051
Fisher, S.E., Vargha-Khadem, F., Watkins, K.E., Monaco, A.P., and Pembrey, M.E., Localisation of a gene implicated in a severe speech and language disorder, Nat. Genet., 1998, vol. 18, p. 168. https://doi.org/10.1038/ng0298-168
Florio, M., Albert, M., Taverna, E., Namba, T., Brandl, H., Lewitus, E., Haffner, C., Sykes, A., Wong, F.K., Peters, J., Guhr, E., Klemroth, S., Prüfer, K., Kelso, J., Naumann, R., et al., Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion, Science, 2015, vol. 347, p. 1465. https://doi.org/10.1126/science.aaa1975
Franchini, L.F. and Pollard, K.S., Human evolution: the non-coding revolution, BMC Biol., 2017, vol. 15, p. 89. https://doi.org/10.1186/s12915-017-0428-9
Girskis, K.M., Stergachis, A.B., DeGennaro, E.M., Doan, R.N., Qian, X., Johnson, M.B., Wang, P.P., Sejourne, G.M., Nagy, M.A., Pollina, E.A., Sousa, A.M.M., Shin, T., Kenny, C.J., Scotellaro, J.L., Debo, B.M., et al., Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions, Neuron, 2021, vol. 109, p. 3239. https://doi.org/10.1016/j.neuron.2021.08.005
Gittelman, R.M., Hun, E., Ay, F., Madeoy, J., Pennacchio, L., Noble, W.S., Hawkins, R.D., and Akey, J.M., Comprehensive identification and analysis of human accelerated regulatory DNA, Genome Res., 2015, vol. 25, p. 1245. https://doi.org/10.1101/gr.192591.115
Guerreiro, I., Nunes, A., Woltering, J.M., Casaca, A., Nóvoa, A., Vinagre, T., Hunter, M.E., Duboule, D., and Mallo, M., Role of a polymorphism in a Hox/Pax-responsive enhancer in the evolution of the vertebrate spine, Proc. Natl. Acad. Sci. U. S. A., 2013, vol. 110, p. 10682. https://doi.org/10.1073/pnas.1300592110
Guidotti, A., Auta, J., Davis, J.M., Di-Giorgi-Gerevini, V., Dwivedi, Y., Grayson, D.R., Impagnatiello, F., Pandey, G., Pesold, C., Sharma, R., Uzunov, D., and Costa, E., Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study, Arch. Gen. Psychiatry, 2000, vol. 57, p. 1061. https://doi.org/10.1001/archpsyc.57.11.1061
Haygood, R., Babbitt, C.C., Fedrigo, O., and Wray, G.A., Contrasts between adaptive coding and noncoding changes during human evolution, Proc. Natl. Acad. Sci. U. S. A., 2010, vol. 107, p. 7853. https://doi.org/10.1073/pnas.0911249107
Herrmann, E., Call, J., Hernàndez-Lloreda, M.V., Hare, B., and Tomasello, M., Humans have evolved specialized skills of social cognition: the cultural intelligence hypothesis, Science, 2007, vol. 317, p. 1360. https://doi.org/10.1126/science.1146282
Hoffman, M.M., Ernst, J., Wilder, S.P., Kundaje, A., Harris, R.S., Libbrecht, M., Giardine, B., Ellenbogen, P.M., Bilmes, J.A., Birney, E., Hardison, R.C., Dunham, I., Kellis, M., and Noble, W.S., Integrative annotation of chromatin elements from ENCODE data, Nucleic Acids Res., 2013, vol. 41, p. 827. https://doi.org/10.1093/nar/gks1284
Huang, J., Perlis, R.H., Lee, P.H., Rush, A.J., Fava, M., Sachs, G.S., Lieberman, J., Hamilton, S.P., Sullivan, P., Sklar, P., Purcell, S., and Smoller, J.W., Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression, Am. J. Psychiatry, 2010, vol. 167, p. 1254. https://doi.org/10.1176/appi.ajp.2010.09091335
Hubisz, M.J. and Pollard, K.S., Exploring the genesis and functions of Human Accelerated Regions sheds light on their role in human evolution, Curr. Opin. Genet. Dev., 2014, vol. 29, p. 15. https://doi.org/10.1016/j.gde.2014.07.005
Hubisz, M.J., Pollard, K.S., and Siepel, A., PHAST and RPHAST: phylogenetic analysis with space/time models, Brief. Bioinform., 2011, vol. 12, p. 41. https://doi.org/10.1093/bib/bbq072
Impagnatiello, F., Guidotti, A.R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M.G., Uzunov, D.P., Smal-heiser, N.R., Davis, J.M., Pandey, G.N., Pappas, G.D., Tueting, P., Sharma, R.P., and Costa, E., A decrease of reelin expression as a putative vulnerability factor in schizophrenia, Proc. Natl. Acad. Sci. U. S. A., 1998, vol. 95, p. 15718. https://doi.org/10.1073/pnas.95.26.15718
Jeffries, A.R., Curran, S., Elmslie, F., Sharma, A., Wenger, S., Hummel, M., and Powell, J., Molecular and phenotypic characterization of ring chromosome 22, Am. J. Med. Genet. A, 2005, vol. 137, p. 139. https://doi.org/10.1002/ajmg.a.30780
Johnson, R., Zuccato, C., Belyaev, N.D., Guest, D.J., Cattaneo, E., and Buckley, N.J., A microRNA-based gene dysregulation pathway in Huntington’s disease, Neurobiol. Dis., 2008, vol. 29, p. 438. https://doi.org/10.1016/j.nbd.2007.11.001
Johnson, M.B., Kawasawa, Y.I., Mason, C.E., Krsnik, Z., Coppola, G., Bogdanović, D., Geschwind, D.H., Mane, S.M., State, M.W., and Sestan, N., Functional and evolutionary insights into human brain development through global transcriptome analysis, Neuron, 2009, vol. 62, p. 494. https://doi.org/10.1016/j.neuron.2009.03.027
Johnson, R., Richter, N., Jauch, R., Gaughwin, P.M., Zuccato, C., Cattaneo, E., and Stanton, L.W., Human accelerated region 1 noncoding RNA is repressed by REST in Huntington’s disease, Physiol. Genomics, 2010, vol. 41, p. 269. https://doi.org/10.1152/physiolgenomics.00019.2010
Kalscheuer, V.M., FitzPatrick, D., Tommerup, N., Bugge, M., Niebuhr, E., Neumann, L.M., Tzschach, A., Shoichet, S.A., Menzel, C., Erdogan, F., Arkesteijn, G., Ropers, H.H., and Ullmann, R., Mutations in autism susceptibility candidate 2 (Auts2) in patients with mental retardation, Hum. Genet., 2007, vol. 121, p. 501. https://doi.org/10.1007/s00439-006-0284-0
Kamm, G.B., López-Leal, R., Lorenzo, J.R., and Franchini, L.F., A fast-evolving human NPAS3 enhancer gained reporter expression in the developing forebrain of transgenic mice, Philos. Trans. R. Soc. London, Ser. B, 2013a, vol. 368, p. 20130019. https://doi.org/10.1098/rstb.2013.0019
Kamm, G.B., Pisciottano, F., Kliger, R., and Franchini, L.F., The developmental brain gene NPAS3 contains the largest number of accelerated regulatory sequences in the human genome, Mol. Biol. Evol., 2013b, vol. 30, p. 1088. https://doi.org/10.1093/molbev/mst023
Kamnasaran, D., Muir, W.J., Ferguson-Smith, M.A., and Cox, D.W., Disruption of the neuronal PAS3 gene in a family affected with schizophrenia, J. Med. Genet., 2003, vol. 40, p. 325. https://doi.org/10.1136/jmg.40.5.325
King, M.C. and Wilson, A.C., Evolution at two levels in humans and chimpanzees, Science, 1975, vol. 188, p. 107. https://doi.org/10.1126/science.1090005
Knable, M.B., Torrey, E.F., Webster, M.J., and Bartko, J.J., Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium, Brain Res. Bull., 2001, vol. 55, p. 651. https://doi.org/10.1016/s0361-9230(01)00521-4
Kvon, E.Z., Kamneva, O.K., Melo, U.S., Barozzi, I., Osterwalder, M., Mannion, B.J., Tissières, V., Pickle, C.S., Plajzer-Frick, I., Lee, E.A., Kato, M., Garvin, T.H., Akiyama, J.A., Afzal, V., Lopez-Rios, J., et al., Progressive loss of function in a limb enhancer during snake evolution, Cell, 2016, vol. 167, p. 633. https://doi.org/10.1016/j.cell.2016.09.028
Lai, C.S., Fisher, S.E., Hurst, J.A., Levy, E.R., Hodg-son, S., Fox, M., Jeremiah, S., Povey, S., Jamison, D.C., Green, E.D., Vargha-Khadem, F., and Monaco, A.P., The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder, Am. J. Hum. Genet., 2000, vol. 67, p. 357. https://doi.org/10.1086/303011
Lai, C.S., Fisher, S.E., Hurst, J.A., Vargha-Khadem, F., and Monaco, A.P., A forkhead-domain gene is mutated in a severe speech and language disorder, Nature, 2001, vol. 413, p. 519. https://doi.org/10.1038/35097076
Lai, C.S., Gerrelli, D., Monaco, A.P., Fisher, S.E., and Copp, A.J., FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder, Brain, 2003, vol. 126, p. 2455. https://doi.org/10.1093/brain/awg247
Lennon, P.A., Cooper, M.L., Peiffer, D.A., Gunderson, K.L., Patel, A., Peters, S., Cheung, S.W., and Bacino, C.A., Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review, Am. J. Med. Genet. A, 2007, vol. 143, p. 791. https://doi.org/10.1002/ajmg.a.31632
Levchenko, A., Kanapin, A., Samsonova, A., and Gainetdinov, R.R., Human accelerated regions and other human-specific sequence variations in the context of evolution and their relevance for brain development, Genome Biol. Evol., 2018, vol. 10, p. 166. https://doi.org/10.1093/gbe/evx240
Li, G., Wang, J., Rossiter, S.J., Jones, G., and Zhang, S., Accelerated FoxP2 evolution in echolocating bats, PLoS One, 2007, vol. 2, p. e900. https://doi.org/10.1371/journal.pone.0000900
Li, Q., Zheng, S., Han, A., Lin, C.H., Stoilov, P., Fu, X.D., and Black, D.L., The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation, Elife, 2014, vol. 3, p. e01201. https://doi.org/10.7554/eLife.01201
Lindblad-Toh, K., Garber, M., Zuk, O., Lin, M.F., Parker, B.J., Washietl, S., Kheradpour, P., Ernst, J., Jordan, G., Mauceli, E., Ward, L.D., Lowe, C.B., Holloway, A.K., Clamp, M., Gnerre, S., et al., A high-resolution map of human evolutionary constraint using 29 mammals, Nature, 2011, vol. 478, p. 476. https://doi.org/10.1038/nature10530
MacDermot, K.D., Bonora, E., Sykes, N., Coupe, A.M., Lai, C.S., Vernes, S.C., Vargha-Khadem, F., McKen-zie, F., Smith, R.L., Monaco, A.P., and Fisher, S.E., Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits, Am. J. Hum. Genet., 2005, vol. 76, p. 1074. https://doi.org/10.1086/430841
Maricic, T., Günther, V., Georgiev, O., Gehre, S., Curlin, M., Schreiweis, C., Naumann, R., Burbano, H.A., Meyer, M., Lalueza-Fox, C., de la Rasilla, M., Rosas, A., Gajovic, S., Kelso, J., Enard, W., et al., A recent evolutionary change affects a regulatory element in the human FOXP2 gene, Mol. Biol. Evol., 2013, vol. 30, p. 844. https://doi.org/10.1093/molbev/mss271
Maurano, M.T., Humbert, R., Rynes, E., Thurman, R.E., Haugen, E., Wang, H., Reynolds, A.P., Sandstrom, R., Qu, H., Brody, J., Shafer, A., Neri, F., Lee, K., Kutyavin, T., Stehling-Sun, S., et al., Systematic localization of common disease-associated variation in regulatory DNA, Science, 2012, vol. 337, p. 1190. https://doi.org/10.1126/science.1222794
Mayor, C., Brudno, M., Schwartz, J.R., Poliakov, A., Rubin, E.M., Frazer, K.A., Pachter, L.S., and Dubchak, I., VISTA: visualizing global DNA sequence alignments of arbitrary length, Bioinformatics, 2000, vol. 16, p. 1046. https://doi.org/10.1093/bioinformatics/16.11.1046
Mitchell, C. and Silver, D.L., Enhancing our brains: genomic mechanisms underlying cortical evolution, Semin. Cell. Dev. Biol., 2018, vol. 76, p. 23. https://doi.org/10.1016/j.semcdb.2017.08.045
Oksenberg, N., Stevison, L., Wall, J.D., and Ahituv, N., Function and regulation of AUTS2, a gene implicated in autism and human evolution, PLoS Genet., 2013, vol. 9, p. e1003221. https://doi.org/10.1371/journal.pgen.1003221
Oswald, F., Klöble, P., Ruland, A., Rosenkranz, D., Hinz, B., Butter, F., Ramljak, S., Zechner, U., and Herlyn, H., The FOXP2-driven network in developmental disorders and neurodegeneration, Front. Cell. Neurosci., 2017, vol. 11, p. 212. https://doi.org/10.3389/fncel.2017.00212
Peñagarikano, O. and Geschwind, D.H., What does CN-TNAP2 reveal about autism spectrum disorder?, Trends Mol. Med., 2012, vol. 18, p. 156. https://doi.org/10.1016/j.molmed.2012.01.003
Pfeiffer, M., Betizeau, M., Waltispurger, J., Pfister, S.S., Douglas, R.J., Kennedy, H., and Dehay, C., Unsupervised lineage-based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ, J. Comp. Neurol., 2016, vol. 524, p. 535. https://doi.org/10.1002/cne.23820
Pickard, B.S., Christoforou, A., Thomson, P.A., Fawkes, A., Evans, K.L., Morris, S.W., Porteous, D.J., Blackwood, D.H., and Muir, W.J., Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder, Mol. Psychiatry, 2009, vol. 14, p. 874. https://doi.org/10.1038/mp.2008.24
Pickard, B.S., Malloy, M.P., Porteous, D.J., Blackwood, D.H., and Muir, W.J., Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability, Am. J. Med. Genet., Part B, 2005, vol. 136, p. 26. https://doi.org/10.1002/ajmg.b.30204
Pilia, G., Hughes-Benzie, R.M., MacKenzie, A., Baybayan, P., Chen, E.Y., Huber, R., Neri, G., Cao, A., Forabosco, A., and Schlessinger, D., Mutations in GPC3, a glypican gene, cause the Simpson–Golabi–Behmel overgrowth syndrome, Nat. Genet., 1996, vol. 12, p. 241. https://doi.org/10.1038/ng0396-241
Pollard, K.S., Hubisz, M.J., Rosenbloom, K.R., and Siepel, A., Detection of nonneutral substitution rates on mammalian phylogenies, Genome Res., 2010, vol. 20, p. 110. https://doi.org/10.1101/gr.097857.109
Pollard, K.S., Salama, S.R., Lambert, N., Lambot, M.A., Coppens, S., Pedersen, J.S., Katzman, S., King, B., Onodera, C., Siepel, A., Kern, A.D., Dehay, C., Igel, H., Ares, M., Vanderhaeghen, P., et al., An RNA gene expressed during cortical development evolved rapidly in humans, Nature, 2006, vol. 443, p. 167. https://doi.org/10.1038/nature05113
Pollen, A.A., Nowakowski, T.J., Chen, J., Retallack, H., Sandoval-Espinosa, C., Nicholas, C.R., Shuga, J., Liu, S.J., Oldham, M.C., Diaz, A., Lim, D.A., Leyrat, A.A., West, J.A., and Kriegstein, A.R., Molecular identity of human outer radial glia during cortical development, Cell, 2015, vol. 163, p. 55. https://doi.org/10.1016/j.cell.2015.09.004
Prabhakar, S., Noonan, J.P., Pääbo, S., and Rubin, E.M., Accelerated evolution of conserved noncoding sequences in humans, Science, 2006, vol. 314, p. 786. https://doi.org/10.1126/science.1130738
Prabhakar, S., Visel, A., Akiyama, J.A., Shoukry, M., Lewis, K.D., Holt, A., Plajzer-Frick, I., Morrison, H., Fitzpatrick, D.R., Afzal, V., Pennacchio, L.A., Rubin, E.M., and Noonan, J.P., Human-specific gain of function in a developmental enhancer, Science, 2008, vol. 321, p. 1346. https://doi.org/10.1126/science.1159974
Rakic, P., Specification of cerebral cortical areas, Science, 1988, vol. 241, p. 170.
Rakic, P., A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution, Trends Neurosci., 1995, vol. 18, p. 383. https://doi.org/10.1016/0166-2236(95)93934-p
Reuter, M.S., Riess, A., Moog, U., Briggs, T.A., Chandler, K.E., Rauch, A., Stampfer, M., Steindl, K., Gläser, D., Joset, P., DDD Study, Krumbiegel, M., Rabe, H., Schulte-Mattler, U., Bauer, P., et al., FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum, J. Med. Genet., 2017, vol. 54, p. 64. https://doi.org/10.1136/jmedgenet-2016-104094
Rice, G.M., Raca, G., Jakielski, K.J., Laffin, J.J., Iyama-Kurtycz, C.M., Hartley, S.L., Sprague, R.E., Heintzelman, A.T., and Shriberg, L.D., Phenotype of FOXP2 haploinsufficiency in a mother and son, Am. J. Med. Genet., Part A, 2012, vol. 158, p. 74. https://doi.org/10.1002/ajmg.a.34354
Schreiber, E., Tobler, A., Malipiero, U., Schaffner, W., and Fontana, A., cDNA cloning of human N-Oct3, a nervous-system specific POU domain transcription factor binding to the octamer DNA motif, Nucleic Acids Res., 1993, vol. 21, p. 253. https://doi.org/10.1093/nar/21.2.253
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., et al., Strong association of de novo copy number mutations with autism, Science, 2007, vol. 316, p. 445. https://doi.org/10.1126/science.1138659
Siepel, A., Bejerano, G., Pedersen, J.S., Hinrichs, A.S., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L.W., Richards, S., Weinstock, G.M., Wilson, R.K., Gibbs, R.A., Kent, W.J., Miller, W., et al., Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes, Genome Res., 2005, vol. 15, p. 1034. https://doi.org/10.1101/gr.3715005
Spiteri, E., Konopka, G., Coppola, G., Bomar, J., Oldham, M., Ou, J., Vernes, S.C., Fisher, S.E., Ren, B., and Geschwind, D.H., Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain, Am. J. Hum. Genet., 2007, vol. 81, p. 1144. https://doi.org/10.1086/522237
Sudmant, P.H., Kitzman, J.O., Antonacci, F., Alkan, C., Malig, M., Tsalenko, A., Sampas, N., Bruhn, L., Shendure, J., Eichler, E.E., and 1000 Genomes Project, Diversity of human copy number variation and multicopy genes, Science, 2010, vol. 330, p. 641. https://doi.org/10.1126/science.1197005
Sullivan, P.F., Kendler, K.S., and Neale, M.C., Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies, Arch. Gen. Psychiatry, 2003, vol. 60, p. 1187. https://doi.org/10.1001/archpsyc.60.12.1187
Suzuki, I.K., Gacquer, D., Van Heurck, R., Kumar, D., Wojno, M., Bilheu, A., Herpoel, A., Lambert, N., Che-ron, J., Polleux, F., Detours, V., and Vanderhaeghen, P., Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation, Cell, 2018, vol. 173, p. 1370. https://doi.org/10.1016/j.cell.2018.03.067
Tomasello, M. and Vaish, A., Origins of human cooperation and morality, Annu. Rev. Psychol., 2013, vol. 64, p. 231. https://doi.org/10.1146/annurev-psych-113011-143812
van Dongen, J. and Boomsma, D.I., The evolutionary paradox and the missing heritability of schizophrenia, Am. J. Med. Genet. B: Neuropsychiatr. Genet., 2013, vol. 162, p. 122. https://doi.org/10.1002/ajmg.b.32135
Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P., and Passingham, R., Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder, Proc. Natl. Acad. Sci. U. S. A., 1995, vol. 92, p. 930. https://doi.org/10.1073/pnas.92.3.930
Varki, A. and Altheide, T.K., Comparing the human and chimpanzee genomes: searching for needles in a haystack, Genome Res., 2005, vol. 15, p. 1746. https://doi.org/10.1101/gr.3737405
Vernes, S.C., Spiteri, E., Nicod, J., Groszer, M., Taylor, J.M., Davies, K.E., Geschwind, D.H., and Fisher, S.E., High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders, Am. J. Hum. Genet., 2007, vol. 81, p. 1232. https://doi.org/10.1086/522238
Veugelers, M., Cat, B.D., Muyldermans, S.Y., Reekmans, G., Delande, N., Frints, S., Legius, E., Fryns, J.P., Schrander-Stumpel, C., Weidle, B., Magdalena, N., and David, G., Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson–Golabi–Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene, Hum. Mol. Genet., 2000, vol. 9, p. 1321. https://doi.org/10.1093/hmg/9.9.1321
Wassink, T.H., Piven, J., Vieland, V.J., Huang, J., Swiderski, R.E., Pietila, J., Braun, T., Beck, G., Folstein, S.E., Haines, J.L., and Sheffield, V.C., Evidence supporting Wnt2 as an autism susceptibility gene, Am. J. Med. Genet., 2001, vol. 105, p. 406. https://doi.org/10.1002/ajmg.1401
Webb, D.M. and Zhang, J., FoxP2 in song-learning birds and vocal-learning mammals, J. Hered., 2005, vol. 96, p. 212. https://doi.org/10.1093/jhered/esi025
Wei, Y., de Lange, S.C., Scholtens, L.H., Watanabe, K., Ardesch, D.J., Jansen, P.R., Savage, J.E., Li, L., Preuss, T.M., Rilling, J.K., Posthuma, D., and van den Heuvel, M.P., Genetic mapping and evolutionary analysis of human-expanded cognitive networks, Nat. Commun., 2019, vol. 10, p. 4839. https://doi.org/10.1038/s41467-019-12764-8
Won, H., de la Torre-Ubieta, L., Stein, J.L., Parikshak, N.N., Huang, J., Opland, C.K., Gandal, M.J., Sutton, G.J., Hormozdiari, F., Lu, D., Lee, C., Eskin, E., Voineagu, I., Ernst, J., and Geschwind, D.H., Chromosome conformation elucidates regulatory relationships in developing human brain, Nature, 2016, vol. 538, p. 523. https://doi.org/10.1038/nature19847
Won, H., Huang, J., Opland, C.K., Hartl, C.L., and Geschwind, D.H., Human evolved regulatory elements modulate genes involved in cortical expansion and neurodevelopmental disease susceptibility, Nat. Commun., 2019, vol. 10, p. 2396. https://doi.org/10.1038/s41467-019-10248-3
Xu, S., Han, J.C., Morales, A., Menzie, C.M., Williams, K., and Fan, Y.S., Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism, Cytogenet. Genome Res., 2008, vol. 122, p. 181. https://doi.org/10.1159/000172086
Xuan, J.Y., Hughes-Benzie, R.M., and MacKenzie, A.E., A small interstitial deletion in the GPC3 gene causes Simpson–Golabi–Behmel syndrome in a Dutch–Canadian family, J. Med. Genet., 1999, vol. 36, p. 57.
Zeesman, S., Nowaczyk, M.J., Teshima, I., Roberts, W., Cardy, J.O., Brian, J., Senman, L., Feuk, L., Osborne, L.R., and Scherer, S.W., Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2, Am. J. Med. Genet., Part A, 2006, vol. 140, p. 509. https://doi.org/10.1002/ajmg.a.31110
Zhang, J., Webb, D.M., and Podlaha, O., Accelerated protein evolution and origins of human-specific features: Foxp2 as an example, Genetics, 2002, vol. 162, p. 1825. https://doi.org/10.1093/genetics/162.4.1825
Zilina, O., Reimand, T., Zjablovskaja, P., Männik, K., Männamaa, M., Traat, A., Puusepp-Benazzouz, H., Kurg, A., and Ounap, K., Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families, Am. J. Med. Genet., Part A, 2012, vol. 158, p. 254. https://doi.org/10.1002/ajmg.a.34378
Zuccato, C. and Cattaneo, E., Role of brain-derived neurotrophic factor in Huntington’s disease, Prog. Neurobiol., 2007, vol. 81, p. 294. https://doi.org/10.1016/j.pneurobio.2007.01.003
ACKNOWLEDGMENTS
The authors are grateful to M.A. Nuriddinov and O.L. Serov (Institute of Cytology and Genetics, Russian Academy of Sciences) for valuable comments on the article.
Funding
This study was financially supported by the Russian Foundation for Basic Research (19-29-04067 mk) and a budget project (no. FWNR-2022-0019).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The authors declare that they have no conflicts of interests. No animals or human beings were involved in this research as subjects.
Additional information
Translated by E. Sherstyuk
Rights and permissions
About this article
Cite this article
Ryzhkova, A.S., Khabarova, A.A., Chvileva, A.S. et al. HARs: History, Functions, and Role in the Evolution and Pathogenesis of Human Diseases. Cell Tiss. Biol. 16, 499–512 (2022). https://doi.org/10.1134/S1990519X22060086
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X22060086