Science China Life Sciences

, Volume 62, Issue 4, pp 526–534 | Cite as

Gain of transcription factor binding sites is associated to changes in the expression signature of human brain and testis and is correlated to genes with higher expression breadth

  • Vandeclécio Lira da Silva
  • André Mauricio Ribeiro dos Santos
  • Wilfredo Blanco
  • Sandro José de SouzaEmail author
Research Paper


The gain of transcription factor binding sites (TFBS) is believed to represent one of the major causes of biological innovation. Here we used strategies based on comparative genomics to identify 21,822 TFBS specific to the human lineage (TFBS-HS), when compared to chimpanzee and gorilla genomes. More than 40% (9,206) of these TFBS-HS are in the vicinity of 1,283 genes. A comparison of the expression pattern of these genes and the corresponding orthologs in chimpanzee and gorilla identified genes differentially expressed in human tissues. These genes show a more divergent expression pattern in the human testis and brain, suggesting a role for positive selection in the fixation of TFBS gains. Genes associated with TFBS-HS were enriched in gene ontology categories related to transcriptional regulation, signaling, differentiation/development and nervous system. Furthermore, genes associated with TFBS-HS present a higher expression breadth when compared to genes in general. This biased distribution is due to a preferential gain of TFBS in genes with higher expression breadth rather than a shift in the expression pattern after the gain of TFBS.


TFBS transcript factor human evolution expression breadth 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



The authors are indebted to Jorge E.S. de Souza for discussions on the gene expression analysis. VLS and AMRS were supported by CAPES Ph.D. fellowships. This work was supported by the Ludwig Institute for Cancer Research and by CAPES (23038.004629/2014-19).

Supplementary material

11427_2018_9454_MOESM1_ESM.xlsx (10 kb)
Supplementary Table 1: Enrichment analysis of transcritpion factors within the set of TFBS-HS
11427_2018_9454_MOESM2_ESM.xlsx (166 kb)
Supplementary Table 2: Differential expression of genes associated to TFBS-HS.


  1. Arbiza, L., Gronau, I., Aksoy, B.A., Hubisz, M.J., Gulko, B., Keinan, A., and Siepel, A. (2013). Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet 45, 723–729.CrossRefGoogle Scholar
  2. Brawand, D., Soumillon, M., Necsulea, A., Julien, P., Csárdi, G., Harrigan, P., Weier, M., Liechti, A., Aximu-Petri, A., Kircher, M., et al. (2011). The evolution of gene expression levels in mammalian organs. Nature 478, 343–348.CrossRefGoogle Scholar
  3. Cunningham, F., Amode, M.R., Barrell, D., Beal, K., Billis, K., Brent, S., Carvalho-Silva, D., Clapham, P., Coates, G., Fitzgerald, S., et al. (2015). Ensembl 2015. Nucleic Acids Res 43, D662–D669.CrossRefGoogle Scholar
  4. Dunham, I., Aldred, S.F., Collins, P.J., Davis, C.A., Doyle, F., Epstein, C. B., Frietze, S., Harrow, J., and Kaul, R. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74.CrossRefGoogle Scholar
  5. Enard, W., Khaitovich, P., Klose, J., Zöllner, S., Heissig, F., Giavalisco, P., Nieselt-Struwe, K., Muchmore, E., Varki, A., Ravid, R., et al. (2002). Intra- and interspecific variation in primate gene expression patterns. Science 296, 340–343.CrossRefGoogle Scholar
  6. Fuchs, T., Gavarini, S., Saunders-Pullman, R., Raymond, D., Ehrlich, M.E., Bressman, S.B., and Ozelius, L.J. (2009). Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 41, 286–288.CrossRefGoogle Scholar
  7. Hurst, L.D., Sachenkova, O., Daub, C., Forrest, A.R.R., Huminiecki, L., and Huminiecki, L. (2014). A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators. Genome Biol 15, 413.CrossRefGoogle Scholar
  8. Kasowski, M., Grubert, F., Heffelfinger, C., Hariharan, M., Asabere, A., Waszak, S.M., Habegger, L., Rozowsky, J., Shi, M., Urban, A.E., et al. (2010). Variation in transcription factor binding among humans. Science 328, 232–235.CrossRefGoogle Scholar
  9. Kent, W.J., Zweig, A.S., Barber, G., Hinrichs, A.S., and Karolchik, D. (2010). BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics 26, 2204–2207.CrossRefGoogle Scholar
  10. Kulikov, A.V., Korostina, V.S., Kulikova, E.A., Fursenko, D.V., Akulov, A. E., Moshkin, M.P., and Prokhortchouk, E.B. (2016). Knockout Zbtb33 gene results in an increased locomotion, exploration and pre-pulse inhibition in mice. Behav Brain Res 297, 76–83.CrossRefGoogle Scholar
  11. Marnetto, D., Molineris, I., Grassi, E., and Provero, P. (2014). Genomewide identification and characterization of fixed human-specific regulatory regions. Am J Hum Genet 95, 39–48.CrossRefGoogle Scholar
  12. Miller, W., Rosenbloom, K., Hardison, R.C., Hou, M., Taylor, J., Raney, B., Burhans, R., King, D.C., Baertsch, R., Blankenberg, D., et al. (2007). 28-Way vertebrate alignment and conservation track in the UCSC Genome Browser. Genome Res 17, 1797–1808.CrossRefGoogle Scholar
  13. Ni, X., Zhang, Y.E., Nègre, N., Chen, S., Long, M., and White, K.P. (2012). Adaptive evolution and the birth of CTCF binding sites in the Drosophila genome. PLoS Biol 10, e1001420.CrossRefGoogle Scholar
  14. Petryszak, R., Burdett, T., Fiorelli, B., Fonseca, N.A., Gonzalez-Porta, M., Hastings, E., Huber, W., Jupp, S., Keays, M., Kryvych, N., et al. (2014). Expression Atlas update—a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments. Nucl Acids Res 42, D926–D932.CrossRefGoogle Scholar
  15. Quinlan, A.R., and Hall, I.M. (2010). BEDTools: A flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842.CrossRefGoogle Scholar
  16. R Core Team. (2013). R: A language and environment for statistical computing. doi:
  17. Rebeiz, M., Castro, B., Liu, F., Yue, F., and Posakony, J.W. (2012). Ancestral and conserved cis-regulatory architectures in developmental control genes. Dev Biol 362, 282–294.CrossRefGoogle Scholar
  18. Ribeiro-dos-Santos, A.M., da Silva, V.L., de Souza, J.E.S., and de Souza, S. J. (2015). Populational landscape of INDELs affecting transcription factor-binding sites in humans. BMC Genom 16, 536.CrossRefGoogle Scholar
  19. Rosenbloom, K.R., Armstrong, J., Barber, G.P., Casper, J., Clawson, H., Diekhans, M., Dreszer, T.R., Fujita, P.A., Guruvadoo, L., Haeussler, M., et al. (2015). The UCSC Genome Browser database: 2015 update. Nucleic Acids Res 43, D670–D681.CrossRefGoogle Scholar
  20. Somel, M., Liu, X., Tang, L., Yan, Z., Hu, H., Guo, S., Jiang, X., Zhang, X., Xu, G., Xie, G., et al. (2011). MicroRNA-driven developmental remodeling in the brain distinguishes humans from other primates. PLoS Biol 9, e1001214.CrossRefGoogle Scholar
  21. Tuğrul, M., Paixão, T., Barton, N.H., and Tkačik, G. (2015). Dynamics of transcription factor binding site evolution. PLoS Genet 11, e1005639.CrossRefGoogle Scholar
  22. Widenius, M., Axmark, D., and DuBois, P. (2002). MySQL reference manual: documentation from the source (Beijing: O’Reilly, Community Press).Google Scholar
  23. Wray, G.A. (2007). The evolutionary significance of cis-regulatory mutations. Nat Rev Genet 8, 206–216.CrossRefGoogle Scholar
  24. Yu, G., Wang, L.G., Han, Y., and He, Q.Y. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287.CrossRefGoogle Scholar
  25. Zhang, W., Landback, P., Gschwend, A.R., Shen, B., and Long, M. (2015). New genes drive the evolution of gene interaction networks in the human and mouse genomes. Genome Biol 16, 202.CrossRefGoogle Scholar
  26. Zhang, Y.E., Landback, P., Vibranovski, M., and Long, M. (2012). New genes expressed in human brains: implications for annotating evolving genomes. Bioessays 34, 982–991.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Vandeclécio Lira da Silva
    • 1
  • André Mauricio Ribeiro dos Santos
    • 1
    • 2
  • Wilfredo Blanco
    • 3
  • Sandro José de Souza
    • 4
    Email author
  1. 1.Bioinformatics Multidisciplinary Environment (BioME)Universidade Federal do Rio Grande do Norte (UFRN)NatalBrazil
  2. 2.Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM)Universidade Federal do Pará (UFPA)BelemBrazil
  3. 3.Department of Computer ScienceUniversidade Estadual do Rio Grande do Norte (UERN)NatalBrazil
  4. 4.Brain InstituteUniversidade Federal do Rio Grande do Norte (UFRN)NatalBrazil

Personalised recommendations