Recurrent sites for new centromere seeding.

Using comparative FISH and genomics, we have studied and compared the evolution of chromosome 3 in primates and two human neocentromere cases on the long arm of this chromosome. Our results show that one of the human neocentromere cases maps to the same 3q26 chromosomal region where a new centromere emerged in a common ancestor of the Old World monkeys approximately 25-40 million years ago. Similarly, the locus in which a new centromere was seeded in the great apes' ancestor was orthologous to the site in which a new centromere emerged in the New World monkeys' ancestor. These data suggest the recurrent use of longstanding latent centromeres and that there is an inherent potential of these regions to form centromeres. The second human neocentromere case (3q24) revealed unprecedented features. The neocentromere emergence was not accompanied by any chromosomal rearrangement that usually triggers these events. Instead, it involved the functional inactivation of the normal centromere, and was present in an otherwise phenotypically normal individual who transmitted this unusual chromosome to the next generation. We propose that the formation of neocentromeres in humans and the emergence of new centromeres during the course of evolution share a common mechanism.

Chromosome 6 phylogeny in primates and centromere repositioning.

A panel of 15 human BAC/PAC probes, covering the entire chromosome 6, was used in FISH experiments on great apes and on representatives of Old World monkeys, New World monkeys, and lemurs to delineate the chromosome 6 phylogeny in primates. The domestic cat was used as an outgroup. The analysis showed a high marker order conservation, with few rearrangements required to reconcile the hypothesized chromosome 6 organization in primate ancestor with marker arrangement in all the examined species. Contrary to this simple evolutionary scenario, however, the centromere was found to be located in three distinct regions, without any evidence of chromosomal rearrangement that would account for its movement. One of the two centromere repositioning events occurred in great apes ancestor. The centromere moved from 6p22.1 to the present day location after the inversion event that differentiated marker order of the primate ancestor from the ancestor of Catarrhini. A cluster of intrachromosomal segmental duplications was found at 6p22.1, scattered in a region of about 9 Mb, which we interpret as remains of duplicons that flanked the ancestral centromere. Our data, therefore, suggest that some duplicon clusters found in noncentromeric/nontelomeric locations may represent traces of evolutionary silenced centromeres that inactivated after the occurrence of a centromere repositioning. In addition, the neocentromere emergence we have documented in Old World monkeys at 6q24.3 appears to have arisen and progressed without affecting the displaced flanking sequences.