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An RNA gene expressed during cortical development evolved rapidly in humans

Abstract

The developmental and evolutionary mechanisms behind the emergence of human-specific brain features remain largely unknown. However, the recent ability to compare our genome to that of our closest relative, the chimpanzee, provides new avenues to link genetic and phenotypic changes in the evolution of the human brain. We devised a ranking of regions in the human genome that show significant evolutionary acceleration. Here we report that the most dramatic of these ‘human accelerated regions’, HAR1, is part of a novel RNA gene (HAR1F) that is expressed specifically in Cajal–Retzius neurons in the developing human neocortex from 7 to 19 gestational weeks, a crucial period for cortical neuron specification and migration. HAR1F is co-expressed with reelin, a product of Cajal–Retzius neurons that is of fundamental importance in specifying the six-layer structure of the human cortex. HAR1 and the other human accelerated regions provide new candidates in the search for uniquely human biology.

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Figure 1: HAR1-associated transcripts in genomic context.
Figure 2: Predicted RNA secondary structure for HAR1F.
Figure 3: Expression of HAR1F and HAR1R in the developing neocortex.
Figure 4: Expression of HAR1F in other parts of the developing brain.

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References

  1. Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Evans, P. D. et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum. Mol. Genet. 13, 489–494 (2004)

    Article  CAS  Google Scholar 

  3. Hill, R. S. & Walsh, C. A. Molecular insights into human brain evolution. Nature 437, 64–67 (2005)

    Article  ADS  CAS  Google Scholar 

  4. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, 1983)

    Book  Google Scholar 

  5. Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005)

    Article  Google Scholar 

  6. Clark, A. G. et al. Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science 302, 1960–1963 (2003)

    Article  ADS  CAS  Google Scholar 

  7. Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005)

    Article  Google Scholar 

  8. Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004)

    Article  CAS  Google Scholar 

  9. Wang, X., Grus, W. E. & Zhang, J. Gene losses during human origins. PLoS Biol. 4, e52 (2006)

    Article  Google Scholar 

  10. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

    Article  ADS  CAS  Google Scholar 

  11. King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975)

    Article  ADS  CAS  Google Scholar 

  12. Pedersen, J. S. et al. Identification and classification of conserved RNA secondary structures in the human genome. PLOS Computat. Biol. 2, e33 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Hillier, L. W. et al. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695–716 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Nobrega, M. A., Ovcharenko, I., Afzal, V. & Rubin, E. M. Scanning human gene deserts for long-range enhancers. Science 302, 413 (2003)

    Article  CAS  Google Scholar 

  16. Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005)

    Article  CAS  Google Scholar 

  17. Hedges, S. B. & Kumar, S. Genomics. Vertebrate genomes compared. Science 297, 1283–1285 (2002)

    Article  CAS  Google Scholar 

  18. Altshuler, D. et al. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

    Article  Google Scholar 

  19. Collins, F. S., Brooks, L. D. & Chakravarti, A. A. DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998)

    Article  CAS  Google Scholar 

  20. Stajich, J. E. & Hahn, M. W. Disentangling the effects of demography and selection in human history. Mol. Biol. Evol. 22, 63–73 (2005)

    Article  CAS  Google Scholar 

  21. Merryman, C. & Noller, H. in RNA–Protein Interactions: A Practical Approach (ed. Smith, C.) 237–253 (Oxford Univ. Press, New York, 1998)

    Google Scholar 

  22. Griffiths-Jones, S. et al. Rfam: Annotating non-coding RNAs in complete genomes. Nucleic Acids Res. 33, D121–D124 (2005)

    Article  CAS  Google Scholar 

  23. Meyer, G. & Goffinet, A. M. Prenatal development of reelin-immunoreactive neurons in the human neocortex. J. Comp. Neurol. 397, 29–40 (1998)

    Article  CAS  Google Scholar 

  24. Meyer, G. & Wahle, P. The paleocortical ventricle is the origin of reelin-expressing neurons in the marginal zone of the foetal human neocortex. Eur. J. Neurosci. 11, 3937–3944 (1999)

    Article  CAS  Google Scholar 

  25. Zecevic, N. & Rakic, P. Development of layer I neurons in the primate cerebral cortex. J. Neurosci. 21, 5607–5619 (2001)

    Article  CAS  Google Scholar 

  26. Meyer, G., Soria, J. M., Martinez-Galan, J. R., Martin-Clemente, B. & Fairen, A. Different origins and developmental histories of transient neurons in the marginal zone of the fetal and neonatal rat cortex. J. Comp. Neurol. 397, 493–518 (1998)

    Article  CAS  Google Scholar 

  27. Rakic, S. & Zecevic, N. Emerging complexity of layer I in human cerebral cortex. Cereb. Cortex 13, 1072–1083 (2003)

    Article  Google Scholar 

  28. Perez-Garcia, C. G., Tissir, F., Goffinet, A. M. & Meyer, G. Reelin receptors in developing laminated brain structures of mouse and human. Eur. J. Neurosci. 20, 2827–2832 (2004)

    Article  CAS  Google Scholar 

  29. Lukaszewicz, A. et al. G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47, 353–364 (2005)

    Article  CAS  Google Scholar 

  30. Bond, J. & Woods, C. G. Cytoskeletal genes regulating brain size. Curr. Opin. Cell Biol. 18, 95–101 (2006)

    Article  CAS  Google Scholar 

  31. Ptak, S. E. et al. Fine-scale recombination patterns differ between chimpanzees and humans. Nature Genet. 37, 429–434 (2005)

    Article  CAS  Google Scholar 

  32. Duret, L., Semon, M., Piganeau, G., Mouchiroud, D. & Galtier, N. Vanishing GC-rich isochores in mammalian genomes. Genetics 162, 1837–1847 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bernardi, G. Isochores and the evolutionary genomics of vertebrates. Gene 241, 3–17 (2000)

    Article  CAS  Google Scholar 

  34. Kudla, G., Lipinski, L., Caffin, F., Helwak, A. & Zylicz, M. High guanine and cytosine content increases mRNA levels in mammalian cells. PLoS Biol. 4, e180 (2006)

    Article  Google Scholar 

  35. Tissir, F. & Goffinet, A. M. Reelin and brain development. Nature Rev. Neurosci. 4, 496–505 (2003)

    Article  CAS  Google Scholar 

  36. Impagnatiello, F. et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl Acad. Sci. USA 95, 15718–15723 (1998)

    Article  ADS  CAS  Google Scholar 

  37. Alfano, G. et al. Natural antisense transcripts associated with genes involved in eye development. Hum. Mol. Genet. 14, 913–923 (2005)

    Article  CAS  Google Scholar 

  38. Lambot, M. A., Depasse, F., Noel, J. C. & Vanderhaeghen, P. Mapping labels in the human developing visual system and the evolution of binocular vision. J. Neurosci. 25, 7232–7237 (2005)

    Article  CAS  Google Scholar 

  39. Depaepe, V. et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435, 1244–1250 (2005)

    Article  ADS  CAS  Google Scholar 

  40. de Bergeyck, V., Naerhuyzen, B., Goffinet, A. M. & Lambert de Rouvroit, C. A panel of monoclonal antibodies against reelin, the extracellular matrix protein defective in reeler mutant mice. J. Neurosci. Methods 82, 17–24 (1998)

    Article  CAS  Google Scholar 

  41. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Bejerano, C. Lowe, J. Kent, H. Noller, D. Feldheim, A. Love (UCSC), V. Albert and J.-C. Noel (Erasme Hospital), J.-P. Brion (ULB), A. Goffinet (UCL Louvain), the UCSC Genome Browser Group, Webb Miller (Penn. State), the Macaque Genome Sequencing Consortium, and the Broad Institute Genome Sequencing Platform and Whole-Genome Assembly Team. This work was funded by the Howard Hughes Medical Institute (D.H., S.R.S. and B.K.), the US NHGRI (D.H., A.D.K., S.K. and C.O.), the US National Cancer Institute (J.S.P.), the US NIGMS (K.S.P. and M.A.), the University of California Biotechnology Research and Education Program (A.S.), the Danish Research Council (J.S.P.), the Belgian FNRS, the Belgian FRSM, the Belgian Queen Elizabeth Medical Foundation (FMRE), the Interuniversity Attraction Poles Programme, Belgian State and Federal Office for Scientific, Technical and Cultural Affairs (P.V.), and the Fondation Erasme (M.-A.L. and N.L.). P.V. and M.-A.L. are Research Associate and Research Fellow of the FNRS, respectively. Author Contributions Computational methods developed and applied by K.S.P., J.S.P., A.S. and A.D.K. Experimental analysis by S.R.S., P.V., N.L., M.-A.L., S.C., S.K., B.K., C.O., C.D., H.I. and M.A. Manuscript primarily written by K.S.P., S.R.S., P.V. and D.H.

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Correspondence to David Haussler.

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The sequences of the HAR1 transcripts reported in this study have been submitted to GenBank (accession numbers DQ860409–DQ860415). Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Pollard, K., Salama, S., Lambert, N. et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443, 167–172 (2006). https://doi.org/10.1038/nature05113

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