title: Human centromeric alphoid domains are periodically homogenized so that they vary substantially between homologues. Mechanism and implications for centromere functioning.
abstract: Sequence analysis of alphoid repeats from human chromosomes 17, 21 and 13 reveals recurrent diagnostic variant nucleotides. Their combinations define haplotypes, with higher order repeats (HORs) containing identical or closely-related haplotypes tandemly arranged into separate domains. The haplotypes found on homologues can be totally different, while HORs remain 99.8% homogeneous both intrachromosomally and between homologues. These results support the hypothesis, never before demonstrated, that unequal crossovers between sister chromatids accumulate to produce homogenization and amplification into tandem alphoid repeats. I propose that the molecular basis of this involves the diagnostic variant nucleotides, which enable pairing between HORs with identical or closely-related haplotypes. Domains are thus periodically renewed to maintain high intrachromosomal and interhomologue homogeneity. The capacity of a domain to form an active centromere is maintained as long as neither retrotransposons nor significant numbers of mutations affect it. In the presented model, a chromosome with an altered centromere can be transiently rescued by forming a neocentromere, until a restored, fully-competent domain is amplified de novo or rehomogenized through the accumulation of unequal crossovers.
authors.affiliation: Institut de Génétique Humaine, UPR 1142, CNRS, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France. roizes@igh.cnrs.fr
authors.forename: Gérard
authors.initials: G
authors.lastname: Roizès
mesh_terms: D002503:Centromere / Q000737:chemistry* / Q000378:metabolism; D002882:Chromosomes, Human, Pair 13 / Q000737:chemistry; D002886:Chromosomes, Human, Pair 17 / Q000737:chemistry; D002891:Chromosomes, Human, Pair 21 / Q000737:chemistry; D004276:DNA, Satellite / Q000737:chemistry*; D006239:Haplotypes; D006801:Humans; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004276:DNA, Satellite