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Regional selection of the brain size regulating gene CASC5 provides new insight into human brain evolution

Abstract

Human evolution is marked by a continued enlargement of the brain. Previous studies on human brain evolution focused on identifying sequence divergences of brain size regulating genes between humans and nonhuman primates. However, the evolutionary pattern of the brain size regulating genes during recent human evolution is largely unknown. We conducted a comprehensive analysis of the brain size regulating gene CASC5 and found that in recent human evolution, CASC5 has accumulated many modern human specific amino acid changes, including two fixed changes and six polymorphic changes. Among human populations, 4 of the 6 amino acid polymorphic sites have high frequencies of derived alleles in East Asians, but are rare in Europeans and Africans. We proved that this between-population allelic divergence was caused by regional Darwinian positive selection in East Asians. Further analysis of brain image data of Han Chinese showed significant associations of the amino acid polymorphic sites with gray matter volume. Hence, CASC5 may contribute to the morphological and structural changes of the human brain during recent evolution. The observed between-population divergence of CASC5 variants was driven by natural selection that tends to favor a larger gray matter volume in East Asians.

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References

  1. Bandelt HJ, Forster P, Rohl A (1999) Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16:37–48

    CAS  Article  PubMed  Google Scholar 

  2. Beals KL, Smith CL, Dodd SM (1984) Brain size, cranial morphology, climate, and time machines. Curr Anthropol 25:30

    Article  Google Scholar 

  3. Bilguvar K et al (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467:207–210

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Bond J et al (2002) ASPM is a major determinant of cerebral cortical size. Nat Genet 32:316–320. doi:10.1038/ng995

    CAS  Article  PubMed  Google Scholar 

  5. Bond J et al (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37:353–355. doi:10.1038/ng1539

    CAS  Article  PubMed  Google Scholar 

  6. Cann RL, Stoneking M, Wilson AC (1987) Mitochondrial DNA and human evolution Nature 325:31–36. doi:10.1038/325031a0

    CAS  PubMed  Google Scholar 

  7. Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT (2004a) Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum Mol Genet 13:1139–1145. doi:10.1093/hmg/ddh126

    CAS  Article  PubMed  Google Scholar 

  8. Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT (2004b) Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13:489–494. doi:10.1093/hmg/ddh055

    CAS  Article  PubMed  Google Scholar 

  9. Evans PD, Vallender EJ, Lahn BT (2006) Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ. Gene 375:75–79. doi:10.1016/j.gene.2006.02.019

    CAS  Article  PubMed  Google Scholar 

  10. Fan CC et al (2015) Modeling the 3D geometry of the cortical surface with genetic ancestry. Curr Biol 25:1988–1992. doi:10.1016/j.cub.2015.06.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Fietz SA et al (2012) Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal. Proc Natl Acad Sci USA 109:11836–11841. doi:10.1073/pnas.1209647109

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Florio M et al (2015) Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science 347:1465–1470. doi:10.1126/science.aaa1975

    CAS  Article  PubMed  Google Scholar 

  13. Genin A et al (2012) Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet 21:5306–5317. doi:10.1093/hmg/dds386

    CAS  Article  PubMed  Google Scholar 

  14. Genomes Project C et al (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073. doi:10.1038/nature09534

    Article  Google Scholar 

  15. Genomes Project C et al (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65. doi:10.1038/nature11632

    Article  Google Scholar 

  16. Goldman N, Yang Z (1994) A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol 11:725–736

    CAS  PubMed  Google Scholar 

  17. Guernsey DL et al (2010) Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am J Hum Genet 87:40–51

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Jablonski NG (2004) The evolution of human skin and skin color. Annu Rev Anthropol 33:585–623. doi:10.1146/annurev.anthro.33.070203.143955

    Article  Google Scholar 

  19. Jackson AP et al (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136–142

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Kiyomitsu T, Obuse C, Yanagida M (2007) Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell 13:663–676. doi:10.1016/j.devcel.2007.09.005

    CAS  Article  PubMed  Google Scholar 

  21. Kline SL, Cheeseman IM, Hori T, Fukagawa T, Desai A (2006) The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation. J Cell Biol 173:9–17. doi:10.1083/jcb.200509158

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Kouprina N et al (2004) Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol 2:E126. doi:10.1371/journal.pbio.0020126

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kumar A, Girimaji SC, Duvvari MR, Blanton SH (2009) Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am J Hum Genet 84:286–290. doi:10.1016/j.ajhg.2009.01.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Li M et al (2012) Meta-analysis and brain imaging data support the involvement of VRK2 (rs2312147) in schizophrenia susceptibility. Schizophr Res 142:200–205. doi:10.1016/j.schres.2012.10.008

    Article  PubMed  Google Scholar 

  25. Li J, Cui Y, Wu K, Liu B, Zhang Y, Wang C, Jiang T (2015) The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking. Neuroimage 117:184–190. doi:10.1016/j.neuroimage.2015.05.033

    Article  PubMed  Google Scholar 

  26. Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452. doi:10.1093/bioinformatics/btp187

    CAS  Article  PubMed  Google Scholar 

  27. Lin S-Y, Elledge SJ (2003) Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113:881–889

    CAS  Article  PubMed  Google Scholar 

  28. McDonald JH, Kreitman M (1991) Adaptive protein evolution at the Adh locus in Drosophila. Nature 351:652–654. doi:10.1038/351652a0

    CAS  Article  PubMed  Google Scholar 

  29. Meyer M et al (2012) A high-coverage genome sequence from an archaic Denisovan individual. Science 338:222–226. doi:10.1126/science.1224344

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Montgomery SH, Capellini I, Venditti C, Barton RA, Mundy NI (2011) Adaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates. Mol Biol Evol 28:625–638. doi:10.1093/molbev/msq237

    CAS  Article  PubMed  Google Scholar 

  31. Nicholas AK et al (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42:1010–1014

    CAS  Article  PubMed  Google Scholar 

  32. Nowaczewska W, Dabrowski P, Kuzminski L (2011) Morphological adaptation to climate in modern Homo sapiens crania: the importance of basicranial breadth. Coll Antropol 35:625–636

    PubMed  Google Scholar 

  33. Pollen AA et al (2015) Molecular identity of human outer radial glia during cortical development. Cell 163:55–67. doi:10.1016/j.cell.2015.09.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Posthuma D, De Geus EJC, Baare WFC, Pol HEH, Kahn RS, Boomsma DI (2002) The association between brain volume and intelligence is of genetic origin. Nat Neurosci 5:83–84. doi:10.1038/Nn0202-83

    CAS  Article  PubMed  Google Scholar 

  35. Posthuma D, Baare WFC, Pol HEH, Kahn RS, Boomsma DI, De Geus EJC (2003) Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Res 6:131–139. doi:10.1375/136905203321536254

    Article  PubMed  Google Scholar 

  36. Prufer K et al (2014) The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505:43–49. doi:10.1038/nature12886

    Article  PubMed  Google Scholar 

  37. Pybus M et al (2014) 1000 Genomes Selection Browser 1.0: a genome browser dedicated to signatures of natural selection in modern humans. Nucleic Acids Res 42:D903–D909. doi:10.1093/nar/gkt1188

    CAS  Article  PubMed  Google Scholar 

  38. Relethford JH (2010) Population-specific deviations of global human craniometric variation from a neutral model. Am J Phys Anthropol 142:105–111. doi:10.1002/ajpa.21207

    Article  PubMed  Google Scholar 

  39. Rimol LM et al (2010) Sex-dependent association of common variants of microcephaly genes with brain structure. Proc Natl Acad Sci USA 107:384–388. doi:10.1073/pnas.0908454107

    CAS  Article  PubMed  Google Scholar 

  40. Roseman CC, Weaver TD (2007) Molecules versus morphology? Not for the human cranium. Bioessays 29:1185–1188. doi:10.1002/bies.20678

    CAS  Article  PubMed  Google Scholar 

  41. Saadi A et al (2016) Refining the phenotype associated with CASC5 mutation. Neurogenetics 17:71–78. doi:10.1007/s10048-015-0468-7

    CAS  Article  PubMed  Google Scholar 

  42. Scheet P, Stephens M (2006) A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78:629–644. doi:10.1086/502802

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Shi L, Lin Q, Su B (2015) Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates. BMC Evol Biol 15:127. doi:10.1186/s12862-015-0398-x

    Article  PubMed  PubMed Central  Google Scholar 

  44. Stulp G, Barrett L (2016) Evolutionary perspectives on human height variation. Biol Rev Camb Philos Soc 91:206–234. doi:10.1111/brv.12165

    Article  PubMed  Google Scholar 

  45. Sturm RA (2009) Molecular genetics of human pigmentation diversity. J Investig Dermatol 129:2920

    Google Scholar 

  46. Szczepanski S et al (2016) A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family. Hum Genet 135:157–170. doi:10.1007/s00439-015-1619-5

    CAS  Article  PubMed  Google Scholar 

  47. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evolut 28:2731–2739. doi:10.1093/molbev/msr121

    CAS  Article  Google Scholar 

  48. Thompson PM et al (2001) Genetic influences on brain structure. Nat Neurosci 4:1253–1258. doi:10.1038/nn758

    CAS  Article  PubMed  Google Scholar 

  49. Wang YQ, Su B (2004) Molecular evolution of microcephalin, a gene determining human brain size. Hum Mol Genet 13:1131–1137. doi:10.1093/hmg/ddh127

    CAS  Article  PubMed  Google Scholar 

  50. Wang JK, Li Y, Su B (2008) A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Hum Mol Genet 17:1329–1335. doi:10.1093/hmg/ddn021

    CAS  Article  PubMed  Google Scholar 

  51. Xu J, Qin W, Liu B, Jiang T, Yu C (2015) Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults. Brain Struct Funct. doi:10.1007/s00429-015-1134-4

    PubMed Central  Google Scholar 

  52. Yang Z (1997) PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13:555–556

    CAS  PubMed  Google Scholar 

  53. Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 24:1586–1591. doi:10.1093/molbev/msm088

    CAS  Article  PubMed  Google Scholar 

  54. Yu TW et al (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42:1015–1020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang J (2003) Evolution of the human ASPM gene, a major determinant of brain size. Genetics 165:2063–2070

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Dr. Martin Kircher from Max Planck Institute for Evolutionary Anthropology for providing the Denisovan’s CASC5 gene sequences and Andrew Willden of the Kunming Institute of Zoology for assistance with the manuscript.

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Correspondence to Bing Su.

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Funding

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13010000), and the National Natural Science Foundation of China (31130051, 31321002, 31123005 and 31301028). This study was also supported by funding from the Youth Innovation Promotion Association of CAS and the State Key Laboratory of Genetic Resources and Evolution (GREKF14-08).

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Additional information

L. Shi, E. Hu and Z. Wang contributed equally to this work.

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Shi, L., Hu, E., Wang, Z. et al. Regional selection of the brain size regulating gene CASC5 provides new insight into human brain evolution. Hum Genet 136, 193–204 (2017). https://doi.org/10.1007/s00439-016-1748-5

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Keywords

  • Brain Size
  • Modern Human
  • East Asian Population
  • Genetic Association Analysis
  • Modern Human Population