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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CASC5 has been found to be associated with gray matter volume differences.
“One of the few genes with several HHMCs, CASC5, has been found to be associated with gray matter volume differences76.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [76]
Cites
Tamura, K., Peterson, D., Peterson, N., Stecher, G., Nei, M., & Kumar, S. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr121 · Cited by 39,795 · see citing works
DnaSP v5: a software for comprehensive analysis of DNA polymorphism data
Librado, P., & Rozas, J. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp187 · Cited by 16,045 · see citing works
PAML 4: Phylogenetic Analysis by Maximum Likelihood
Yang, Z. (2007) · Molecular Biology and Evolution · doi:10.1093/molbev/msm088 · Cited by 13,879 · see citing works
Median-joining networks for inferring intraspecific phylogenies
Bandelt, H. J., Forster, P., & Rohl, A. (1999) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a026036 · Cited by 11,742 · see citing works
A map of human genome variation from population-scale sequencing.
The 1000 Genomes Project Consortium (2010) · Nature · doi:10.1038/nature09534 · Cited by 7,877 · see citing works
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711 · see citing works
PAML: a program package for phylogenetic analysis by maximum likelihood
Yang, Z. (1997) · Computer applications in the biosciences · doi:10.1093/bioinformatics/13.5.555 · Cited by 5,344 · see citing works
Adaptive protein evolution at the Adh locus in Drosophila
McDonald, J. H., & Kreitman, M. (1991) · Nature · doi:10.1038/351652a0 · Cited by 3,320 · see citing works
Mitochondrial DNA and human evolution
Cann, R. L., Stoneking, M., & Wilson, A. C. (1987) · Nature · doi:10.1038/325031a0 · Cited by 3,100 · see citing works
The complete genome sequence of a Neanderthal from the Altai Mountains
Prüfer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., Heinze, A., Renaud, G., Sudmant, P. H., de Filippo, C., et al. (2014) · Nature · doi:10.1038/nature12886 · Cited by 2,254 · see citing works
A high-coverage genome sequence from an archaic denisovan individual
Meyer, M., Kircher, M., Gansauge, M.-T., Li, H., Racimo, F., Mallick, S., Schraiber, J. G., Jay, F., Prüfer, K., de Filippo, C., et al. (2012) · Science · doi:10.1126/science.1224344 · Cited by 1,967 · see citing works
A codon-based model of nucleotide substitution for protein-coding DNA sequences.
(1994) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040153 · Cited by 1,960 · see citing works
Scheet, P. A., & Stephens, M. (2006) · The American Journal of Human Genetics · doi:10.1086/502802 · Cited by 1,949 · see citing works
Genetic influences on brain structure
Thompson, P. M., Cannon, T. D., Narr, K. L., van Erp, T. G. M., Poutanen, V.-P., HUTTUNEN, M. O., Lönnqvist, J. K., Standertskjöld-Nordenstam, C.-G., Kaprio, J. A., Khaledy, M., et al. (2001) · Nature Neuroscience · doi:10.1038/nn758 · Cited by 1,033 · see citing works
Molecular Identity of Human Outer Radial Glia during Cortical Development
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., et al. (2015) · Cell · doi:10.1016/j.cell.2015.09.004 · Cited by 908 · see citing works
Human-specific gene <i>ARHGAP11B</i> promotes basal progenitor amplification and neocortex expansion
Florio, M., Albert, M., Taverna, E., Namba, T., Brandl, H., Lewitus, E., Haffner, C., Sykes, A., Wong, F. K., Peters, J., et al. (2015) · Science · doi:10.1126/science.aaa1975 · Cited by 632 · see citing works
ASPM is a major determinant of cerebral cortical size
Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., et al. (2002) · Nature Genetics · doi:10.1038/ng995 · Cited by 581 · see citing works
A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size
Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J. W., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., et al. (2005) · Nature Genetics · doi:10.1038/ng1539 · Cited by 564 · see citing works
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
Bilgüvar, K., Öztürk, A. K., Louvi, A., Kwan, K. Y., Choi, M., Tatlı, B., Yalnızoğlu, D., Tüysüz, B., Çağlayan, A. O., Gökben, S., et al. (2010) · Nature · doi:10.1038/nature09327 · Cited by 503 · see citing works
Identification of microcephalin, a protein implicated in determining the size of the human brain
Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/341283 · Cited by 482 · see citing works
Multiple Tumor Suppressor Pathways Negatively Regulate Telomerase
Lin, S., & Elledge, S. J. (2003) · Cell · doi:10.1016/s0092-8674(03)00430-6 · Cited by 427 · see citing works
Molecular genetics of human pigmentation diversity
Sturm, R. A. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp003 · Cited by 379 · see citing works
The evolution of human skin and skin color
Jablonski, N. G. (2004) · Annual Review of Anthropology · doi:10.1146/annurev.anthro.33.070203.143955 · Cited by 367 · see citing works
The association between brain volume and intelligence is of genetic origin
Posthuma, D., De Geus, E. J. C., Baaré, W. F. C., Pol, H. E. H., Kahn, R. S., & Boomsma, D. I. (2002) · Nature Neuroscience · doi:10.1038/nn0202-83 · Cited by 356 · see citing works
Fietz, S. A., Lachmann, R., Brandl, H., Kircher, M., Samusik, N., Schröder, R., Lakshmanaperumal, N., Henry, I., Vogt, J., Riehn, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209647109 · Cited by 337 · see citing works
Brain Size, Cranial Morphology, Climate, and Time Machines [and Comments and Reply]
Beals, K. L., Smith, C. L., Dodd, S. M., Angel, J. L., Armstrong, E., Blumenberg, B., Girgis, F. G., Turkel, S., Gibson, K. R., Henneberg, M., et al. (1984) · Current Anthropology · doi:10.1086/203138 · Cited by 332 · see citing works
Kiyomitsu, T., Obuse, C., & Yanagida, M. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.09.005 · Cited by 301 · see citing works
WDR62 is associated with the spindle pole and is mutated in human microcephaly
Nicholas, A. K., Khurshid, M., Désir, J., Carvalho, O. P., Cox, J. J., Thornton, G., Kausar, R., Ansar, M., Ahmad, W., Verloès, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.682 · Cited by 297 · see citing works
Yu, T. W., Mochida, G. H., Tischfield, D. J., Sgaier, S. K., Flores‐Sarnat, L., Sergi, C. M., Topçu, M., McDonald, M., Barry, B. J., Felie, J. M., et al. (2010) · Nature Genetics · doi:10.1038/ng.683 · Cited by 294 · see citing works
Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans
Evans, P. D., Anderson, J. R., Vallender, E. J., Gilbert, S. L., Malcom, C. M., Dorus, S., & Lahn, B. T. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh055 · Cited by 240 · see citing works
Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly
Kumar, A., Girimaji, S. C., Duvvari, M. R., & Blanton, S. H. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.01.017 · Cited by 231 · see citing works
Evolutionary perspectives on human height variation
Stulp, G., & Barrett, L. (2014) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12165 · Cited by 224 · see citing works
Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size
Evans, P. D. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh126 · Cited by 220 · see citing works
The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation
Kline-Smith, S. L., Cheeseman, I. M., Hori, T., Fukagawa, T., & Desai, A. B. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200509158 · Cited by 213 · see citing works
Evolution of the HumanASPMGene, a Major Determinant of Brain Size
Zhang, J. (2003) · Genetics · doi:10.1093/genetics/165.4.2063 · Cited by 206 · see citing works
Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4
Guernsey, D. L., Jiang, H., Hussin, J., Arnold, M., Bouyakdan, K., Perry, S., Babineau-Sturk, T., Beis, J., Dumas, N., Evans, S. C., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.06.003 · Cited by 200 · see citing works
Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion
Kouprina, N., Pavlı́ček, A., Mochida, G. H., Solomon, G. G., Gersch, W., Yoon, Y.-H., Collura, R. V., Ruvolo, M., Barrett, J. C., Woods, C. G., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020126 · Cited by 194 · see citing works
Molecular evolution of microcephalin, a gene determining human brain size
Wang, Y., & Su, B. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh127 · Cited by 150 · see citing works
Self-citationAdaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates
Montgomery, S. H., Capellini, I., Venditti, C., Barton, R. A., & Mundy, N. I. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msq237 · Cited by 143 · see citing works
Danielle Posthuma, B., Baaré, W. F. C., Pol, H. E. H., Kahn, R. S., Boomsma, D. I., & de Geus, E. J. C. (2003) · Twin Research · doi:10.1375/136905203321536254 · Cited by 139 · see citing works
Pybus, M., Dall’Olio, G. M., Luisi, P., Uzkudun, M., Torres, A. C., Pavlidis, P., Laayouni, H., Bertranpetit, J., & Engelken, J. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1188 · Cited by 138 · see citing works
Molecules versus morphology? Not for the human cranium
Roseman, C. C., & Weaver, T. D. (2007) · BioEssays · doi:10.1002/bies.20678 · Cited by 119 · see citing works
Kinetochore KMN network gene CASC5 mutated in primary microcephaly
Genin, A., Desir, J., Lambert, N., Biervliet, M., Van Der Aa, N., Pierquin, G., Killian, A., Tosi, M., Urbina, M., Lefort, A., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds386 · Cited by 116 · see citing works
Sex-dependent association of common variants of microcephaly genes with brain structure
Rimol, L. M., Agartz, I., Djurovic, S., Brown, A. A., Roddey, J. C., Kähler, A. K., Mattingsdal, M., Athanasiu, L., Joyner, A. H., Schork, N. J., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908454107 · Cited by 111 · see citing works
Population‐specific deviations of global human craniometric variation from a neutral model
Relethford, J. H. (2009) · American Journal of Physical Anthropology · doi:10.1002/ajpa.21207 · Cited by 92 · see citing works
Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ
Evans, P. D., Vallender, E. J., & Lahn, B. T. (2006) · Gene · doi:10.1016/j.gene.2006.02.019 · Cited by 84 · see citing works
A common SNP of MCPH1 is associated with cranial volume variation in Chinese population
Wang, J., Li, Y., & Su, B. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn021 · Cited by 53 · see citing works
Self-citationLi, M., Wang, Y., Zheng, X.-B., Ikeda, M., Iwata, N., Luo, X., Chong, S. A., Lee, J., Rietschel, M., Zhang, F., et al. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.10.008 · Cited by 47 · see citing works
Self-citationModeling the 3D Geometry of the Cortical Surface with Genetic Ancestry
Fan, C. C., Bartsch, H., Schork, A. J., Chen, C., Wang, Y., Lo, M., Brown, T. T., Kuperman, J. M., Hagler, D. J., Schork, N. J., et al. (2015) · Current Biology · doi:10.1016/j.cub.2015.06.006 · Cited by 40 · see citing works
Szczepanski, S., Hussain, M. S., Sur‐Erdem, İ., Altmüller, J., Thiele, H., Abdullah, U., Waseem, S. S., Moawia, A., Nürnberg, G., Noegel, A. A., et al. (2015) · Human Genetics · doi:10.1007/s00439-015-1619-5 · Cited by 37 · see citing works
Refining the phenotype associated with CASC5 mutation
Saadi, A., Verny, F., Siquier-Pernet, K., Bôle‐Feysot, C., Nitschké, P., Münnich, A., Abada-Dendib, M., Chaouch, M., Abramowicz, M., & Colleaux, L. (2015) · Neurogenetics · doi:10.1007/s10048-015-0468-7 · Cited by 23 · see citing works
Xu, J., Qin, W., Liu, B., Jiang, T., & Yu, C. (2015) · Brain Structure and Function · doi:10.1007/s00429-015-1134-4 · Cited by 18 · see citing works
Self-citationEstrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates
Shi, L., Lin, Q., & Su, B. (2015) · BMC Evolutionary Biology · doi:10.1186/s12862-015-0398-x · Cited by 15 · see citing works
Self-citationNowaczewska, W., Dąbrowski, P., & Kuźmiński, Ł. (2011) · PubMed · Cited by 9 · see citing works
The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking
Li, J., Cui, Y. J., Wu, K. L., Liu, B., Zhang, Y., Wang, C., & Jiang, T. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.05.033 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
2 of the 57 references couldn’t be matched to a known paper.
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A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
Kuhlwilm, M., & Boeckx, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-44877-x · Cited by 108 · see citing works
“One of the few genes with several HHMCs, CASC5, has been found to be associated with gray matter volume differences (Shi et al. 2017).”
Parallel pathways for recruiting effector proteins determine centromere drive and suppression
Kumon, T., Ma, J., Akins, R. B., Stefanik, D. J., Nordgren, E. C., Kim, J., Levine, M. T., & Lampson, M. A. (2021) · Cell · doi:10.1016/j.cell.2021.07.037 · Cited by 76 · see citing works
Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype
Omer Javed, A., Li, Y., Muffat, J., Su, K.-C., Cohen, M. A., Lungjangwa, T., Aubourg, P., Cheeseman, I. M., & Jaenisch, R. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.032 · Cited by 46 · see citing works
DNA damage and repair: underlying mechanisms leading to microcephaly
Ribeiro, J. H., Altinisik, N., Rajan, N., Verslegers, M., Baatout, S., Gopalakrishnan, J., & Quintens, R. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1268565 · Cited by 23 · see citing works
Evolution of eukaryotic centromeres by drive and suppression of selfish genetic elements
Kumon, T., & Lampson, M. A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.03.026 · Cited by 18 · see citing works
Herculano‐Houzel, S. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.06.001 · Cited by 15 · see citing works
Romero, V., Arias‐Almeida, B., & Aguiar, S. A. (2022) · BMC Genomics · doi:10.1186/s12864-022-09071-w · Cited by 8 · see citing works
Primary microcephaly with an unstable genome
Xu, S., Wu, X., Peng, B., Cao, S., & Xu, X. (2020) · Genome Instability & Disease · doi:10.1007/s42764-020-00020-z · Cited by 7 · see citing works
On the Problem of the Interpretation of Symbols and Symbolism in Archaeology
Coolidge, F. L., Overmann, K. A., & Wynn, T. A. (2023) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780192895950.013.1 · Cited by 6 · see citing works
D40/KNL1/CASC5 and autosomal recessive primary microcephaly
Takimoto, M. (2017) · Congenital Anomalies · doi:10.1111/cga.12252 · Cited by 5 · see citing works
Centromere drive and suppression by parallel pathways for recruiting microtubule destabilizersPreprint
Kumon, T., Ma, J., Stefanik, D. J., Nordgren, E. C., Akins, R. B., Kim, J., Levine, M. T., & Lampson, M. A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.26.400515 · Cited by 3 · see citing works
Congenital and postnatal microcephalies
Lim, Y., & Golden, J. A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814409-1.00016-1 · Cited by 1 · see citing works
Zhang, Z., Zhang, S., & Xu, Y. (2024) · Research Square · doi:10.21203/rs.3.rs-5430247/v1 · Cited by 1 · see citing works
Adaptive Evolution of Microcephaly Genes
Montgomery, S. H. (2019) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0028393
Boyarsky, K. Y., Скобеева, В. А., Chekhonina, O. B., & Инвериевна, К. Е. (2022) · Genes and Cells · doi:10.23868/202205009
ADN, histoire de nos différences
(2020) · Odile Jacob eBooks · doi:10.3917/oj.sablo.2020.01.0231
Xia, W., Geng, Y., Zhang, S., Xu, Y., & Zhang, Z. (2024) · Advances in computer science research · doi:10.2991/978-94-6463-447-1_47
Zhang, Z., Zhang, S., & Xu, Y. (2025) · Academia molecular biology and genomics. · doi:10.20935/acadmolbiogen8001 · Cited by 1 · see citing works
Romero, V., Arias‐Almeida, B., & Aguiar, S. A. (2023) · Figshare · doi:10.6084/m9.figshare.22604875
What makes human cortex human? Rephrasing the question to consider numbers of neurons
Herculano-Houzel, S. (2026) · Evolution of Nervous Systems · doi:10.1016/b978-0-443-27380-3.00079-8
- Authors
- Shi, L., Hu, E., Wang, Z., Liu, J., Li, J., Li, M., Chen, H., Yu, C., Jiang, T., & Su, B.
- Affiliations
- Kunming Institute of Zoology (CN)
- Chinese Academy of Sciences (CN)
- Johns Hopkins University (US)
- Tianjin Medical University General Hospital (CN)
- University of Electronic Science and Technology of China (CN)
- Corresponding author
- Su, Bing
- Venue
- Human Genetics
- Published
- 2016-11-22
- Volume
- 136
- Issue
- 2
- Pages
- 193-204
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- OpenAlex
- W2553400254
- Cited by
- 20
- References
- 57
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 1
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31130051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Keywords
- human brain evolution, positive selection, regional selection, amino acid polymorphism, gray matter volume, East Asian populations, Han Chinese, brain structure
- MeSH terms
- Adult, Alleles, Animals, Brain, Pan troglodytes, Biological Evolution, Female, Gene Expression Regulation, Gene Frequency, Haplotypes, Humans, Image Processing, Computer-Assisted, Macaca, Magnetic Resonance Imaging, Male, Microtubule-Associated Proteins, Middle Aged, Organ Size, Selection, Genetic, Linkage Disequilibrium, Genome, Human, Linear Models, Sequence Alignment, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Asian People, Young Adult, Genetic Fitness, Genotyping Techniques, Gray Matter
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