Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

Centromeric Repeats of the Western European House Mouse II: Selection for High Local Diversity of Monomers and a Hypothesis for Coevolution between Centromere Size and Karyotype Number

Version 1 : Received: 8 September 2020 / Approved: 17 September 2020 / Online: 17 September 2020 (12:13:03 CEST)

How to cite: Rice, W. Centromeric Repeats of the Western European House Mouse II: Selection for High Local Diversity of Monomers and a Hypothesis for Coevolution between Centromere Size and Karyotype Number. Preprints 2020, 2020090407 (doi: 10.20944/preprints202009.0407.v1). Rice, W. Centromeric Repeats of the Western European House Mouse II: Selection for High Local Diversity of Monomers and a Hypothesis for Coevolution between Centromere Size and Karyotype Number. Preprints 2020, 2020090407 (doi: 10.20944/preprints202009.0407.v1).

Abstract

The companion paper (Rice 2020) found that the centromeric repeats of the Western European house mouse (Mus musculus domesticus) have unusual structure: i) despite moderate pairwise sequence divergence (average = 5.9%), no monomer sequence was common and many hundreds of monomer sequences were observed, ii) local sequence divergence among neighboring monomers was nearly as high as genome-wide divergence, and iii) matching sequences were rare between side-by-side monomers. Here I integrate information from many published studies to formulate a hypothesis for the evolution of this structure. Non-matching sequences of neighboring centromeric monomers is hypothesized to be selectively favored in the context of molecular drive because it reduces the rate of monomer deletion during repair of double strand breaks (DSBs) via the Single Strand Annealing (SSA) pathway. The foundation for the hypothesis is the observation that centromeres of most populations of M. m. domestics reside close to the telomere, i.e., all their chromosomes are telocentrics. This proximity influences repair of centromeric DSBs because it places at least part of the centromere within the Telomere-Affected Repair Region (TARR; a location with increased concentrations of the shelterin-complex proteins that bind telomeres, especially TRF2). Shelterin proteins increase the level of 5’3’ end resection at DSBs and thereby: i) decrease the frequency of repair via the c- NHEJ pathway, and ii) increase the frequency of homology-directed repair (HD-repair) –including the SSA repair pathway. It is hypothesized that certain ‘trigger’ events (e.g., sub-telomeric deletions) occur in local populations that increase the influence of TARR on the centromere. This increase elevates the occurrence of SSA repair of centromeric DSBs to a level that causes centromeres to begin to gradually shrink. Chronic shrinkage leads to coevolution between centromere size and karyotype number. Once centromeres shrink to a size below a critical minimum (that causes substantially reduced kinetochore size), fusions between non- homologous telocentrics with undersized centromeres produces metacentrics with an expanded centromere size (and a corresponding ‘quantum-jump’ in kinetochore size). These metacentrics: i) accumulate to fixation because they are favored by centromere drive, and ii) are released from the influence of TARR and thereby gradually recover larger centromere size. Fission of metacentrics with enlarged centromeres can next plausibly regenerate pairs of telocentrics with sufficiently large centromeres (which recruit normal-sized kinetochores) to be favored by centromere drive and accumulate to fixation. This fixation completes a cycle of coevolution within genomes that oscillate between two extremes: i) high karyotype number (2N = 40; all telocentrics) with larger centromeres, and ii) low karyotype number (2N << 40; mainly metacentrics) with initially small centromeres that gradually increase in size.

Subject Areas

Centromere; karyotype evolution; centromere drive; Mus musculus domesticus

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