Genomic and Genetic Definition of a Functional Human Centromere

Abstract

The definition of centromeres of human chromosomes requires a complete genomic understanding of these regions. Toward this end, we report integration of physical mapping, genetic, and functional approaches, together with sequencing of selected regions, to define the centromere of the human X chromosome and to explore the evolution of sequences responsible for chromosome segregation. The transitional region between expressed sequences on the short arm of the X and the chromosome-specific alpha satellite array DXZ1 spans about 450 kilobases and is satellite-rich. At the junction between this satellite region and canonical DXZ1 repeats, diverged repeat units provide direct evidence of unequal crossover as the homogenizing force of these arrays. Results from deletion analysis of mitotically stable chromosome rearrangements and from a human artificial chromosome assay demonstrate that DXZ1 DNA is sufficient for centromere function. Evolutionary studies indicate that, while alpha satellite DNA present throughout the pericentromeric region of the X chromosome appears to be a descendant of an ancestral primate centromere, the current functional centromere based on DXZ1 sequences is the product of the much more recent concerted evolution of this satellite DNA.

Clusters of alpha satellite on human chromosome 21 are dispersed far onto the short arm and lack ancient layers

“…Both types of monomeric clusters contain a lower frequency of transposed elements compared to the rest of the genome but do possess a higher frequency of such elements compared to HOR arrays , Schueler et al 2001, Kazakov et al 2003. This is consistent with monomeric AS clusters being older than HOR arrays but having a more recent history than the rest of the genome.…”

Analysis of a t(18;21)(p11.1;p11.1) translocation in a family with schizophrenia

“…21 The pericentric region represents a bridge between the heterochromatic centromere sequences and euchromatic DNA. The short arms of acrocentric chromosomes, such as 21 are also characterized by satellite DNAs I, II, III, IV and b.…”

Pericentric and centromeric transcription: a perfect balance required

“…Most complex eukaryotic centromeres have not been traversed and fully assembled by modern sequencing technology, but are known to be composed of highly repetitive sequences, mainly satellites and retroelements (Schueler et al 2001;Jiang et al 2003;Dawe and Henikoff 2006;Birchler et al 2011). While the function of the centromere is evolutionarily conserved in all forms of life, the DNA sequences and several of the corresponding DNA binding proteins found at centromeres are rapidly evolving.…”