Adaptive Evolution of Centromeric Proteins


Kinetochore proteins assemble at centromeres and mediate chromosome segregation during eukaryotic cell division. This conserved function conceals a paradox; essential inner kinetochore proteins, CenH3 and CENP‐C, evolve rapidly under positive selection in primates, plants and insects. This paradox may be explained by a genetic conflict between selfish DNA sequences at the centromere and the kinetochore proteins that bind them. The centromere drive hypothesis provides a framework for understanding this conflict and makes predictions for patterns of evolution in the composition of the kinetochore. In contrast with the rapidly evolving inner kinetochore, the components of the outer kinetochore do not make contacts with centromeric DNA and evolve more slowly. Furthermore, genetic conflict at the centromere may underlie observed taxonomic differences in the rate of evolution of kinetochore proteins among species with different meiotic programs.

Key Concepts:

  • Despite an essential and conserved function, some centromere‐binding proteins evolve rapidly.

  • In contrast to canonical histone H3, the centromeric variant of histone H3 displays striking patterns of positive selection in functionally critical domains.

  • CENP‐C displays rapid evolution across a diverse taxa; the functional consequences of this rapid evolution have not yet been studied.

  • Asymmetric female meiosis provides an opportunity for competition among centromeres for evolutionary success but has deleterious consequences in male meiosis leading to genetic conflict.

  • Genetic conflict between centromeres and centromere‐binding proteins can explain the divergent patterns of evolution between inner and outer kinetochore proteins, as well as taxonomic differences in rapid evolution of centromeric proteins.

Keywords: centromeres; chromatin; rapid evolution; gene duplication; outer kinetochore; fibrous corona; microtubules; female meiosis; mitosis

Figure 1.

Kinetochore formation and structure (Cheeseman and Desai, ). (a) After DNA replication and cell division the Mis18 complex prepares centromeric chromatin for additional CenH3 deposition. It is unknown whether a chaperone is universally required for proper CenH3 loading, but many species encode CenH3 chaperones (Scm3/HJURP) that are essential for CenH3 deposition. (b) The CCAN proteins form the structure of the inner kinetochore, directly binding both centromeric DNA and nucleosomes containing CenH3. The CCAN forms the attachment site for the proteins of outer kinetochore and fibrous corona, acting as a link between the centromeric DNA and the rest of the kinetochore. (c) The outer kinetochore and fibrous corona binds the CCAN at the beginning of mitosis. Proteins of the fibrous corona regulate the spindle checkpoint and ensure proper microtubule binding before dissociating from the kinetochore. The complexes of the outer kinetochore remain throughout mitosis and provide mechanism for microtubules to transmit force to the chromosome.

Figure 2.

Centromeric histones differ from canonical histone H3 in sequence and function. (a) Canonical histones are highly conserved, whereas CenH3 are highly divergenced. The variation of the N‐terminal tail of CenH3 is so great that it is not possible to align these features across taxa. (b) Loop 1 domains within the histone fold domain also vary in sequence and length in CenH3s but not canonical H3 proteins. (c) A crystal structure of the histone fold domains of the CenH3 (blue)/ H4 (yellow) heterotetramer (Sekulic et al., ). The amino acids of the rapidly evolving, centromere‐targeting loop 1 are highlighted in red.

Figure 3.

CENP‐C proteins show little homology across taxa. (a) CENP‐C evolves so rapidly that only a 24 amino‐acids domain (referred to as the CENP‐C domain) is homologous between widely diverged species. More closely related species share larger regions of homology. The amino and C‐terminal regions are homologous throughout vertebrates, with a smaller carboxyl motif also present in fungi. Plants share only the CENP‐C motif with animals but have their own homologous region in the N‐terminus (Talbert et al., ). (b) In addition to the rapid evolution in amino acid sequence, CENP‐C is experiencing repeated exon duplication and deletion. Cereal crops have undergone duplication and subsequent deletion of exons 8 and 9. This deletion is followed by repeated duplication and loss of adjacent exons 10 and 11 (Talbert et al., ).



Amano M, Suzuki A, Hori T et al. (2009) The CENP‐S complex is essential for the stable assembly of outer kinetochore structure. Journal of Cell Biology 186(2): 173–182.

Barnhart MC, Kuich PH, Stellfox ME et al. (2011) HJURP is a CENP‐A chromatin assembly factor sufficient to form a functional de novo kinetochore. Journal of Cell Biology 194(2): 229–243.

Black BE and Cleveland DW (2011) Epigenetic centromere propagation and the nature of CENP‐a nucleosomes. Cell 144(4): 471–479.

Black BE, Foltz DR, Chakravarthy S et al. (2004) Structural determinants for generating centromeric chromatin. Nature 430(6999): 578–582.

Black BE, Jansen LET, Foltz DR and Cleveland DW (2007) Centromere identity maintained by nucleosomes assembled with histone H3 containing the CENP‐A targeting domain. Molecular Cell 25(2): 309–322.

Buttrick GJ and Millar JB (2011) Ringing the changes: emerging roles for DASH at the kinetochore‐microtubule interface. Chromosome Research 19(3): 393–407.

Camahort R, Li B, Flores L et al. (2007) Scm3 is essential to recruit the histone h3 variant cse4 to centromeres and to maintain a functional kinetochore. Molecular Cell 26(6): 853–865.

Camahort R, Shivaraju M, Mattingly M et al. (2009) Cse4 is part of an octameric nucleosome in budding yeast. Molecular Cell 35(6): 794–805.

Casola C, Hucks D and Feschotte C (2008) Convergent domestication of pogo‐like transposases into centromere‐binding proteins in fission yeast and mammals. Molecular Biology and Evolution 25(1): 29–41.

Cheeseman IM, Brew C, Wolyniak M et al. (2001) Implication of a novel multiprotein Dam1p complex in outer kinetochore function. Journal of Cell Biology 155(7): 1137–1145.

Cheeseman IM, Chappie JS, Wilson‐Kubalek E and Desai A (2006) The conserved KMN network constitutes the core microtubule‐binding site of the kinetochore. Cell 127(5): 983–997.

Cheeseman IM and Desai A (2008) Molecular architecture of the kinetochore–microtubule interface. Nature Reviews Molecular Cell Biology 9(1): 33–46.

Cheeseman IM, Hori T, Fukagawa T et al. (2008) KNL1 and the CENP‐H/I/K complex coordinately direct kinetochore assembly in vertebrates. Molecular Biology of the Cell 19(2): 587–594.

Conde e Silva N, Black BE, Sivolob A et al. (2007) CENP‐A‐containing nucleosomes: easier disassembly versus exclusive centromeric localization. Journal of Molecular Biology 370(3): 555–573.

Cooper J L and Henikoff S (2004) Adaptive evolution of the histone fold domain in centromeric histones. Molecular Biology and Evolution 21(9): 1712–1718.

Dalal Y, Furuyama T, Vermaak D and Henikoff S (2007a) Structure, dynamics, and evolution of centromeric nucleosomes. Proceedings of the National Academy of Sciences of the USA 104(41): 15974–15981.

Dalal Y, Wang H, Lindsay S and Henikoff S (2007b) Tetrameric structure of centromeric nucleosomes in interphase Drosophila cells. Plos Biology 5(8): e218.

Daniel A (2002) Distortion of female meiotic segregation and reduced male fertility in human Robertsonian translocations: consistent with the centromere model of co‐evolving centromere DNA/centromeric histone (CENP‐A). American Journal of Medical Genetics 111(4): 450–452.

Desai A, Rybina S, Moller‐Reicher T et al. (2003) KNL‐1 directs assembly of the microtubule‐binding interface of the kinetochore in C. elegans. Genes & Development 17(19): 2421–2435.

Du Y, Topp CN and Dawe RK (2010) DNA binding of centromere protein C (CENPC) is stabilized by single‐stranded RNA. PLoS Genetics 6(2): e1000835.

Dunleavy EM, Roche D, Tagami H et al. (2009) HJURP is a cell‐cycle‐dependent maintenance and deposition factor of CENP‐A at centromeres. Cell 137(3): 485–497.

Earnshaw WC and Migeon BR (1985) Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome. Chromosoma 92(4): 290–296.

Elde NC, Roach KC, Yao M‐C and Malik HS (2011) Absence of positive selection on centromeric histones in tetrahymena suggests unsuppressed centromere‐drive in lineages lacking male meiosis. Journal of Molecular Evolution 72(5‐6): 510–520.

Fishman L and Saunders A (2008) Centromere‐associated female meiotic drive entails male fitness costs in monkeyflowers. Science 322(5907): 1559–1562.

Foltz DR, Jansen LE, Bailey AO et al. (2009) Centromere‐specific assembly of CENP‐a nucleosomes is mediated by HJURP. Cell 137(3): 472–484.

Fujita Y, Hayashi T, Kiyomitsu T et al. (2007) Priming of centromere for CENP‐A recruitment by human hMis18alpha, hMis18beta, and M18BP1. Developmental Cell 12(1): 17–30.

Fukagawa T, Pendon C, Morris J and Brown W (1999) CENP‐C is necessary but not sufficient to induce formation of a functional centromere. The EMBO Journal 18(15): 4196–4209.

Han F, Lamb JC and Birchler JA (2006) High frequency of centromere inactivation resulting in stable dicentric chromosomes of maize. Proceedings of the National Academy of Sciences of the USA 103(9): 3238–3243.

Hayashi T, Fujita Y, Iwasaki O et al. (2004) Mis16 and Mis18 are required for CENP‐A loading and histone deacetylation at centromeres. Cell 118(6): 715–729.

Henikoff S, Ahmad K and Malik HS (2001) The centromere paradox: stable inheritance with rapidly evolving DNA. Science 293(5532): 1098–1102.

Henikoff S and Furuyama T (2010) Epigenetic inheritance of centromeres. Cold Spring Harbor Symposia on Quantitative Biology 75: 51–60.

Henikoff S and Malik HS (2002) Centromeres: selfish drivers. Nature 417(6886): 227.

Heun P, Erhardt S, Blower MD et al (2006) Mislocalization of the Drosophila centromere‐specific histone CID promotes formation of functional ectopic kinetochores. Developmental Cell 10(3): 303–315.

Hori T, Amano M, Suzuki A et al. (2008) CCAN makes multiple contacts with centromeric DNA to provide distinct pathways to the outer kinetochore. Cell 135(6): 1039–1052.

Lampert F and Westermann S (2011) A blueprint for kinetochores – new insights into the molecular mechanics of cell division. Nature Reviews Molecular Cell Biology 12(7): 407–412.

Malik HS and Henikoff S (2003) Phylogenomics of the nucleosome. Nature Structural Biology 10(11): 882–891.

Malik HS and Henikoff S (2009) Major evolutionary transitions in centromere complexity. Cell 138(6): 1067–1082.

Malik HS, Vermaak D and Henikoff S (2002) Recurrent evolution of DNA‐binding motifs in the Drosophila centromeric histone. Proceedings of the National Academy of Sciences of the USA 99(3): 1449–1454.

Masumoto H, Masukata H, Muro Y, Nozaki N and Okazaki T (1989) A human centromere antigen (CENP‐B) interacts with a short specific sequence in alphoid DNA, a human centromeric satellite. The Journal of Cell Biology 109(5): 1963–1973.

Mellone BG, Grive KJ, Shteyn V et al. (2011) Assembly of Drosophila centromeric chromatin proteins during mitosis. PLoS Genetics 7(5): e1002068.

Miranda JJ, De Wulf P, Sorger PK and Harrison SC (2005) The yeast DASH complex forms closed rings on microtubules. Nature Structural & Molecular Biology 12(2): 138–143.

Nezi L and Musacchio A (2009) Sister chromatid tension and the spindle assembly checkpoint. Current Opinion in Cell Biology 21(6): 785–795.

Ohzeki J‐I, Nakano M, Okada T and Masumoto H (2002) CENP‐B box is required for de novo centromere chromatin assembly on human alphoid DNA. The Journal of Cell Biology 159(5): 765–775.

Orr B and Sunkel CE (2011) Drosophila CENP‐C is essential for centromere identity. Chromosoma 120(1): 83–96.

Palmer DK, O'Day K, Trong HL, Charbonneau H and Margolis RL (1991) Purification of the centromere‐specific protein CENP‐A and demonstration that it is a distinctive histone. Proceedings of the National Academy of Sciences of the USA 88(9): 3734–3738.

Panchenko T and Black BE (2009) The epigenetic basis for centromere identity. In: Ugarkovic D (ed.) Centromere, vol. 48. pp. 1–32. Heidelberg, Berlin: Springer.

Pardo‐Manuel de Villena F and Sapienza C (2001) Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations. Human Genetics 108(1): 31–36.

Perpelescu M and Fukagawa T (2011) The ABCs of CENPs. Chromosoma 120(5): 425–446.

Petrovic A, Pasqualato S, Dube P et al. (2010) The MIS12 complex is a protein interaction hub for outer kinetochore assembly. The Journal of Cell Biology 190(5): 835–852.

Politi V, Perini G, Trazzi S et al. (2002) CENP‐C binds the alpha‐satellite DNA in vivo at specific centromere domains. Journal of Cell Science 115(Pt 11): 2317–2327.

Powers AF, Franck AD, Gestaut DR et al. (2009) The Ndc80 kinetochore complex forms load‐bearing attachments to dynamic microtubule tips via biased diffusion. Cell 136(5): 865–875.

Ravi M, Kwong PN, Minorca RMG et al. (2010) The rapidly evolving centromere‐specific histone has stringent functional requirements in Arabidopsis thaliana. Genetics 186(2): 461–471.

Sanchez‐Pulido L, Pidoux AL, Ponting CP and Allshire RC (2009) Common ancestry of the CENP‐A chaperones Scm3 and HJURP. Cell 137(7): 1173–1174.

Sardar HS, Luczak VG, Lopez MM, Lister BC and Gilbert SP (2010) Mitotic kinesin CENP‐E promotes microtubule plus‐end elongation. Current Biology 20(18): 1648–1653.

Schittenhelm RB, Althoff F, Heidmann S and Lehner CF (2010) Detrimental incorporation of excess Cenp‐A/Cid and Cenp‐C into Drosophila centromeres is prevented by limiting amounts of the bridging factor Cal1. Journal of Cell Science 123(Pt 21): 3768–3779.

Schueler MG, Swanson W, Thomas PJ NISC Comparative Sequencing Project and Green ED (2010) Adaptive evolution of foundation kinetochore proteins in primates. Molecular Biology and Evolution 27(7): 1585–1597.

Sekulic N, Bassett EA, Rogers BJ and Black BE (2010) The structure of (CENP‐A‐H4)(2) reveals physical features that mark centromeres. Nature 467(7313): 347–351.

Shuaib M, Ouararhni K, Dimitrov S and Hamiche A (2010) HJURP binds CENP‐A via a highly conserved N‐terminal domain and mediates its deposition at centromeres. Proceedings of the National Academy of Sciences of the USA 107(4): 1349–1354.

Stoler S, Rogers K, Weitze S et al. (2007) Scm3, an essential Saccharomyces cerevisiae centromere protein required for G2/M progression and Cse4 localization. Proceedings of the National Academy of Sciences of the USA 104(25): 10571–10576.

Tachiwana H, Kagawa W, Shiga T et al. (2011) Crystal structure of the human centromeric nucleosome containing CENP‐A. Nature, 476(7359): 232–235.

Talbert PB, Bryson TD and Henikoff S (2004) Adaptive evolution of centromere proteins in plants and animals. Journal of Biology 3(4): 18.

Talbert PB, Masuelli R, Tyagi AP, Comai L and Henikoff S (2002) Centromeric localization and adaptive evolution of an Arabidopsis histone H3 variant. Plant Cell 14(5): 1053–1066.

Trazzi S, Perini G, Bernardoni R et al. (2009) The C‐terminal domain of CENP‐C displays multiple and critical functions for mammalian centromere formation. PLoS ONE 4(6): e5832.

van Valen L (1973) A new evolutionary law. Evolutionary Theory 1: 1–30.

Vermaak D, Hayden HS and Henikoff S (2002) Centromere targeting element within the histone fold domain of Cid. Molecular and Cellular Biology 22(21): 7553–7561.

Warburton PE, Cooke CA, Bourassa S et al. (1997) Immunolocalization of CENP‐A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Current Biology 7(11): 901–904.

Williams B, Leung G, Maiato H et al. (2007) Mitch – a rapidly evolving component of the Ndc80 kinetochore complex required for correct chromosome segregation in Drosophila. Journal of Cell Science 120(20): 3522–3533.

Zhou Z, Feng H, Zhou B‐R et al. (2011) Structural basis for recognition of centromere histone variant CenH3 by the chaperone Scm3. Nature 472(7342): 234–237.

Further Reading

Amor DJ, Kalitsis P, Sumer H et al. (2004) Building the centromere: from foundation proteins to 3D organization. Trends in Cell Biology 14(7): 359–368.

Choo KHA (1997) The Centromere. New York: Oxford University Press.

Verdaasdonk JS and Bloom K (2011) Centromeres: unique chromatin structures that drive chromosome segregation. 12(5): 320–332.

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Roach, Kevin C, Ross, Benjamin D, and Malik, Harmit S(Nov 2011) Adaptive Evolution of Centromeric Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022868]