Centromeres are essential chromosomal structures that mediate the accurate distribution of genetic material during meiotic and mitotic cell divisions. In most organisms, centromeres are epigenetically specified and propagated by nucleosomes containing the centromere-specific H3 variant, centromere protein A (CENP-A). Although centromeres perform a critical and conserved function, CENP-A and the underlying centromeric DNA are rapidly evolving. This paradox has been explained by the centromere drive hypothesis, which proposes that CENP-A is undergoing an evolutionary tug-of-war with selfish centromeric DNA. Here, we review our current understanding of CENP-A evolution in relation to centromere drive and discuss classical and recent advances, including new evidence implicating CENP-A chaperones in this conflict.

The interaction between CAL1 and CENP-A is flexible, but the rapid evolution of CENP-A in flies has resulted in species-specific co-evolution of CAL1 to maintain centromere identity.

The failure of a subset of CENP-A orthologs from other species to localize to centromeres in Drosophila melanogaster cells can be explained by an incompatibility with the CENP-A chaperone CAL1, rather than centromeric DNA.

CENP-A chaperones in flies have recently been implicated in this evolutionary arms race.

It is unknown whether CENP-A can regulate the transmission rate of a centromere by modulating its binding preferences for certain DNA sequences.

The amounts of centromeric and kinetochore proteins recruited to one centromere influence its likelihood to be transmitted via the female germ line in mice.

CENP-A and centromeric DNA have been proposed to co-evolve in an evolutionary tug-of-war known as centromere drive.

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Evidence for Dobzhansky-Muller incompatibilites contributing to the sterility of hybrids between Mimulus guttatus and M. nasutus.

A role for the CAL1-partner Modulo in centromere integrity and accurate chromosome segregation in Drosophila.

The effect of multiple simple Robertsonian heterozygosity on chromosome pairing and fertility of wild-stock house mice (Mus musculus domesticus).

Centromere strength provides the cell biological basis for meiotic drive and karyotype evolution in mice.

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).

Differential role of CENP-A in the segregation of holocentric C. elegans chromosomes during meiosis and mitosis.

Absence of positive selection on CenH3 in Luzula suggests that holokinetic chromosomes may suppress centromere drive.

Genetic variation in rates of nondisjunction: association of two naturally occurring polymorphisms in the chromokinesin nod with increased rates of nondisjunction in Drosophila melanogaster.

Detrimental incorporation of excess Cenp-A/Cid and Cenp-C into Drosophila centromeres is prevented by limiting amounts of the bridging factor Cal1.

Evolutionary insights into the role of the essential centromere protein CAL1 in Drosophila.

How can satellite DNA divergence cause reproductive isolation? Let us count the chromosomal ways.

Centromeres take flight: alpha satellite and the quest for the human centromere.

Something from nothing: the evolution and utility of satellite repeats.

The N terminus of the centromere H3-like protein Cse4p performs an essential function distinct from that of the histone fold domain.

Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere.

Scm3 is essential to recruit the histone H3 variant Cse4 to centromeres and to maintain a functional kinetochore.

Loading of Arabidopsis centromeric histone CENH3 occurs mainly during G 2 and requires the presence of the histone fold domain.

The cell cycle timing of centromeric chromatin assembly in Drosophila meiosis is distinct from mitosis yet requires CAL1 and CENP-C.

Two distinct pathways responsible for the loading of CENP-A to centromeres in the fission yeast cell cycle.

H3.3 is deposited at centromeres in S phase as a placeholder for newly assembled CENP-A in G 1 phase.

Centromere identity in Drosophila is not determined in vivo by replication timing.

Both tails and the centromere targeting domain of CENP-A are required for centromere establishment.

Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres.

Identification of centromeric antigens in dicentric robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres.

Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome.

Recurrent loss of CenH3 is associated with independent transitions to holocentricity in insects.

Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma.

A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis.

Glossary

171-bp sequences arranged into a higher-order repeat structure found at the centromere region of higher primate species.

when two proteins evolve in concert, possibly as a result of genetic conflict.

a chromosome containing two centromere regions, one of which is usually inactive, originated via the fusion of two chromosomes segments each containing a centromere.

a centromere located at a novel chromosomal position relative to the ancestral centromere in that lineage. ENCs are devoid of satellite DNA and other centromeric repeats but contain CENP-A.

when different genes or loci influence the same phenotype, and the transmission of one locus is increased due to its phenotypic effects being more favorable, causing a subsequent decrease in transmission of the other gene/locus. This conflict can be within an individual (intragenomic) or between individuals (intergenomic).

the transformation of euchromatin (active chromatin) into heterochromatin (inactive). This process usually involves epigenetic modification through the recruitment of histone methyl-transferases and histone deacetylases.

the distortion from Mendelian ratios of allelic inheritance in heterozygotes during meiosis. Female meiotic drive, also known as chromosomal drive, occurs via competition among homologous chromosomes for inclusion in the egg, the only surviving product of meiosis. Male meiotic drive often acts postmeiotically.

refers to a type of selective pressure where the ratio of non-synonymous substitutions to synonymous substitutions for a given gene is less than 1 (dN/dS < 1), indicating that selection acts against changes within this protein. Also known as purifying selection.

a functional centromere that forms at a non-centromeric locus.

refers to a type of selective pressure where the ratio of non-synonymous substitutions to synonymous substitutions for a given gene is greater than 1 (dN/dS > 1), indicating that certain mutations changing the amino acid composition are selected for.

also known as Robertsonian translocations, occur when two acrocentric or telocentric chromosomes (i.e., with centromeres at or near the end of the chromosome, respectively) fuse at their centromere, resulting in a large chromosome with two adjacent centromeres in the middle.

a region of DNA that enhances its own transmission, often at the expense of the organism as a whole.