Centromere Repositioning

We discovered this phenomenon while studying the evolutionary history of human chromosome 9 in primates (8). Figure 1 summarizes the results obtained using a panel of yeast artificial chromosome clones used to establish marker order along this chromosome in 9 different primate species. If the position of the centromere is not taken into account, a relatively small number of rearrangements can be invoked to reconstruct the marker order in the studied species. Conversely, if the centromere is included in the analysis, a paradox emerges: the centromere appears to have undergone an independent evolutionary history. We hypothesized that the movement of the centromere toward the new location was not owing to classical chromosomal rearrangements (essentially inversions), but, rather, to the inactivation of the old centromere and the simultaneous appearance of a new centromere in a different location. The complexity of the evolutionary history of chromosome 9 did not allow certain alternative hypotheses to be discarded, such as two successive inversions, the first involving the centromere and the second restoring the previous marker order with the exception of the centromere.

For these reasons we undertook similar studies on other chromosomes. According to Ohno's law, the gene content of the chromosome X has barely changed throughout mammalian development in the last 125 million years (9). The X chromosome was, therefore, an ideal chromosome in this respect. The position of the centromere of this chromosome is substantially unchanged in primates, with two exceptions in prosimians: the black lemur (Eulemur macaco [EMA]), and the ring-tailed lemur (Lemur catta [LCA]). The chromosome X appears acrocentric in black lemur and almost metacentric in ring-tailed lemur (Fig. 2). We investigated the marker order organization using a variety of different molecular cytogenetic tools, but no variation in marker order was found (10). We concluded that the move of the centromere in EMA and LCA was because of the centromere repositioning event.

Fig. 1. Summary of fluorescence in situ hybridization results delineating the evolutionary history of human chromosome 9 in primates. The hypothesized pericentric or paracentric inversions are indicated by brackets spanning the inverted segment. The brackets at the bottom of the figure groups species in which the difference in centromere position cannot be explained on the basic of classical rearrangements. Species studied: common chimpanzee (Pan troglodytes, PTR), gorilla (Gorilla gorilla, GGO), and orangutan (Pongo pygmaeus, PPY). Old World monkeys, silvered leaf-monkey (Presbytis cristata, PCR). New World monkeys, dusky titi (Callicebus molloch, CMO), spider monkey (Ateles geoffroyi); common marmoset (Callithrix jacchus, CJA), and squirrel monkey (Saimiri sciureus, SSC). (Adapted with permission from ref. 8.)

Fig. 1. Summary of fluorescence in situ hybridization results delineating the evolutionary history of human chromosome 9 in primates. The hypothesized pericentric or paracentric inversions are indicated by brackets spanning the inverted segment. The brackets at the bottom of the figure groups species in which the difference in centromere position cannot be explained on the basic of classical rearrangements. Species studied: common chimpanzee (Pan troglodytes, PTR), gorilla (Gorilla gorilla, GGO), and orangutan (Pongo pygmaeus, PPY). Old World monkeys, silvered leaf-monkey (Presbytis cristata, PCR). New World monkeys, dusky titi (Callicebus molloch, CMO), spider monkey (Ateles geoffroyi); common marmoset (Callithrix jacchus, CJA), and squirrel monkey (Saimiri sciureus, SSC). (Adapted with permission from ref. 8.)

A centromere repositioning implies the inactivation of an ancestral centromere and the seeding of a new centromere. Neocentromere appearance is not a rare event in human. Human neocentromeres are defined as "rare human chromosomal aberrations where a new centromere has formed in a previously non-centromeric location" (11). The first well-documented case of a human neocentromere was reported by du Sart et al. (12). Since then, more than 50 neocentromere cases have been described (13). Some neocentromeres are clustered in "hotspots" for neocentromere formation, which include 3q26-qter, 8p, 13q21-q32, and 15q24-q26 regions. Most of the neocentromeres arise in acentric fragments because of a cytogenetic rearrangement. Acentric chromosomal fragments are usually lost. However, in some cases, their mitotic survival is rescued by neocentromere appearance, which is always an accidental event with respect to the rearrangement. In two cases, the neocentromere that emerged on chromosome

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