A Game of Thrones at Human Centromeres II. A new molecular/evolutionary model

Abstract

Human centromeres are remarkable in four ways: they are i) defined epigenetically by an elevated concentration of the histone H3 variant CENP-A, ii) inherited epigenetically by trans-generational cary-over of nucleosomes containing CENP-A, iii) formed over unusually long and complex tandem repeats (Higher Order Repeats, HORs) that extend over exceptionally long arrays of DNA (up to 8 Mb), and iv) evolve in such a rapid and punctuated manner that most HORs on orthologous chimp and human chromosomes are in different clades. What molecular and evolutionary processes generated these distinctive characteristics? Here I motivate and construct a new model for the formation, expansion/contraction, homogenization and rapid evolution of human centromeric repeat arrays that is based on fork-collapse during DNA replication (in response to proteins bound to DNA and/or collisions between DNA and RNA polymerases) followed by out-of-register re-initiation of replication via Break-Induced Repair (BIR). The model represents a new form of molecular drive. It predicts rapid and sometimes punctuated evolution of centromeric HORs due to a new form of intragenomic competition that is based on two features: i) the rate of tandem copy number expansion, and ii) resistance to invasion by pericentric heterochromatin within a centromere’s HOR array. These features determine which variant array elements will eventually occupy a pivotal region within a centromeric repeat array (switch-point) that gradually expands to populate the entire array. In humans, continuous HOR turnover is predicted due to intra-array competition between three repeat types with an intransitive hierarchy: A < B < C < A, where A = short, single-dimer HORs containing one monomer that binds centromere protein-B (CENP-B) and another that does not, B = moderately longer HORs composed of ≥ 2 dimers, and C = substantially longer HORs that lose their dimeric modular structure. Continuous turnover of proteins that bind centromeric DNA (but these proteins are not constituents of the kinetochore) and polygenic variation influencing position-effect variegation are predicted to cause rapid turnover of centromeric repeats in species lacking HORs and/or CENP-B binding at centromeres. Evolution at centromeres is a molecular ‘Game-of-Thrones’ because centromeric sequences ‘reign’ due to an epigenetic ‘crown’ of CENP-A that is perpetually ‘usurped’ by new sequences that more rapidly assemble large ‘armies’ of tandem repeats and/or resist ‘invasion’ from a surrounding ‘frontier’ of percentric heterochromatin. These ‘regal transitions’ occur in a backdrop of slashing and decapitation (fork-collapse generating truncated sister chromatids) in the context of promiscuous sex that is frequently incestuous (out-of-register BIR between sibling chromatids).