The fragile centromere

Human centromeres are long stretches of repetitive DNA located at the primary constriction of human chromosomes. Specialized nucleosomes containing the histone H3 variant, CENP-A, serve as basal template for the assembly of the human kinetochore for faithful chromosome segregation. Recent functional studies, long-read sequencing and new reference genomes have finally enabled the exploration of these complex sequences. For the first time, the mechanisms underlying the origin, evolution, and preservation of centromeric repeats are coming into view. The dual dynamics of preservation and rapid evolution are encapsulated by our recent discovery of a stable centromere architecture despite underlying divergence, implying strong selection to maintain the overall repeat structure while tolerating high rates of sequence variation across species, individuals, and between maternal and paternal haplotypes in each person. Here, I review the latest technological and conceptual advances that are fueling exploration of human centromere organization and maintenance, including stabilizing and destabilizing forces within the kinetochore binding site. Intrinsic propensity to secondary structures synergizing with the sudden drop in methylation at the functional locus can, during DNA-based transactions, cause breaks, with ensuing rearrangements and chromosomal arm-level events that perturb overall genome integrity. The (epi)genetic information 'written' within centromeres reveals the footprint of DNA repair pathways and mutational processes. I propose recombination-driven repeat homogenization to be a form of antagonistic pleiotropy, where array uniformity benefits kinetochore assembly and meiotic transmission at the cost of dynamic somatic changes, chromosomal rearrangements and genome instability that can drive cancer etiology.