A Game of Thrones at Human Centromeres I. Multifarious structure necessitates a new molecular/evolutionary model

Rice, William R.

doi:10.1101/731430

Cited by 14 publications

(33 citation statements)

References 102 publications

(66 reference statements)

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“…The multifarious structure seen at the centromeric HORs of human chromosomes was used to generate a hypothesis for the evolution of centromeric HORs (Figure 2; see Figure 10 in Rice 2019 for a fuller description). This hypothesis describes a cycle that has has five steps: i) HORs begin as simple b/n-box dimers (a pair of monomers, one containing a b-box sequence (that binds CENP-B) in the linker separating nucleosomes, and the other containing a n-box sequence (that does not bind CENP-B) at this position, ii) HORs then grow (add monomers), but only by adding additional b/n-box dimer units, iii) once sufficiently large, HORs continue to grow, but start losing modular b/n-box dimer structure by adding lone monomers and mutating b-boxes so that they no longer bind CENP-B, iv) after losing substantial dimeric structure, HORs are replaced (by a new b/n-box d i m e r H O R ) b e c a u s e t h e y r e c r u i t substantially less CENP-C, and v) replaced, inactive HOR arrays ultimately go extinct due to recurrent deletion pressure While the main goal of this paper is to integrate information from many sources to deduce a new model for centromere evolution that is consistent will the multifarious structure reported (Rice 2019), a second goal is to evaluate this hypothesis.…”

Section: Hypothesis For An Evolutionary Cycle Of Hor Expansion and Rementioning

confidence: 80%

“…My objective is not to provide a model for centromere evolution that is correct in all details -I expect some details of the model to evolve as new information accrues over time. Instead, I will motivate a feasible foundation (starting point) for a new model of centromere evolution that is based on fork-stalling, fork-collapse and Break-Induced Repair (BIR) during DNA replication (rather than the unequal crossing over of the Smith model) and that is consistent with the many levels of structure that I identified in the companion paper (Rice 2019).…”

Section: Introductionmentioning

confidence: 86%

“…A new foundation for the rapid evolution of human centromeric HORs: replication fork-collapse followed by out-of-register BIR The Smith model of repeat evolution (via unequal crossover between sister chromatids) does not predict the apparent cycle of HOR structure described in the above section, nor many of the structural characteristics found at human centromeric repeats (see Box 1 in the companion paper [Rice 2019]). An example of one of the inconsistencies between the Smith model and empirical data is the observed large size of HOR arrays (usually [2][3] Mb [Willard 1991], but sometimes exceeding 8 Mb [Miga et al 2014]), compared to the minimum size required for cellular functioning (50-100 Kb; Lo et al 1999;Yang et al 2000;Okamoto et al 2007).…”

Section: Hypothesis For An Evolutionary Cycle Of Hor Expansion and Rementioning

confidence: 99%

“…HORs with modular b/n-box dimer structure are predicted to recruit maximal CENP-C The pattern of monomers observed at the full set of human HORs (across all chromosomes) indicates that their composition has structural constraints (Rice 2019). The strongly predominant unit found in active human HORs is the b/n-box dimer, and shorter HORs (those with 10 or fewer monomers) are made up almost exclusively of these dimers (see Figure 7 of the companion paper, Rice 2019).…”

Section: Influence Of Modular B/n-box Dimer Structurementioning

confidence: 99%

“…The Smith model is a neutral model of evolution that predicts that the DNA sequence of the repeats seen in satellite DNAs will be effectively random -except for the avoidance of intrinsically harmful sequences, such those that form secondary structure that interferes with DNA replication. In the companion paper (Rice 2019), I showed that the human HORs found at active centromeric repeat arrays across all 24 chromosomes are highly structured at multiple levels, and that this structure could feasibly come from some sort of functional constraint that is not predicted by the Smith (1976) model. I also showed that the exceptionally large sizes of centromeric HOR arrays (far larger than required for cellular functioning), and their observed patterns of length variation on the sex chromosomes, indicate that some process other than unequal crossing over (between sister chromatids) is responsible for generating most length variation at centromeric arrays and driving the rapid evolution of centromeric HORs.…”

Section: Introductionmentioning

confidence: 99%

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

Rice

2019

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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).

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Section: Hypothesis For An Evolutionary Cycle Of Hor Expansion and Rementioning

confidence: 80%

Section: Introductionmentioning

confidence: 86%

Section: Hypothesis For An Evolutionary Cycle Of Hor Expansion and Rementioning

confidence: 99%

Section: Influence Of Modular B/n-box Dimer Structurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Rice

2019

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Centromeric repeats of the Western European house mouse I: high sequence diversity among monomers at local and global spatial scales

Rice

2020

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Previous work found that the centromeric repeats of the Western European house mouse (Mus musculus domesticus) are composed predominantly of a 120 bp monomer that is shared by the X and autosomes. Polymorphism in length and sequence was also reported. Here I quantified the length and sequence polymorphism of the centromeric repeats found on the X and autosomes. The levels of local and global sequence variation were also compared. I found three length variants: a 64mer, 112mer and 120mer with relative frequencies of 2.4%, 8.6%, and 89%, respectively. There was substantial sequence variation within all three length variants with a rank-order of: 64mer < 120mer < 112mer. The 64mer was never found alone on long Sanger traces, and was arranged predominantly as a 176 bp higher-order repeat composed of a 64/112mer dimer. Reanalysis of archived ChIP-seq reads found that all three length variants were enriched with the foundational centromere protein CENP-A, but the enrichment was far higher for the 120mer. This pattern indicates that only the 120mer contributes substantially to the functional centromeres, i.e., to the kinetochore-binding, centric cores of the centromeric repeat arrays. Despite only moderate sequence divergence among random pairs of 120mers (averaging 5.9%), other measures of sequence diversity were exceptionally high: i) variant richness (numerical diversity) –on average, one new sequence variant was observed every 4th additional monomer randomly sampled (in N = 7.2 × 103 monomers), and ii) variant evenness –all of the nearly 2 × 103 observed sequence variants were at low frequency, with the most common variant having a frequency of only 5.7%. I next used long Sanger trace data from the Mouse Genome Project to assess the pattern of monomer diversity among neighboring 120mers. Unexpectedly, side-by-side monomers were rarely identical in sequence, and sequence divergence between these neighbors was nearly as high as that between random pairs taken from the genome-wide pool of all 120mers. I also used long Sanger traces to determine sequence variation among neighborhoods of 5 contiguous 120 bp monomers. Sequence diversity within these small regions typically spanned most of the entire range of that found genome-wide. Despite high sequence variation within these neighborhoods, the density of monomers with functional binding motifs for CENP-B (i.e., b-boxes with sequence NTTCGNNNNANNCGGGN) was strongly conserved at about 50%. The overarching pattern of monomer structure at the centromeric repeats of this subspecies is: i) high homogeneity in the density CENP-B binding sites, and ii) high heterogeneity in monomer sequence at both local and global levels.

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HORmon: automated annotation of human centromeres

Kunyavskaya

Dvorkina

Bzikadze

et al. 2021

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Recent advances in long-read sequencing opened a possibility to address the long-standing questions about the architecture and evolution of human centromeres. They also emphasized the need for centromere annotation (partitioning human centromeres into monomers and higher-order repeats (HORs)). Even though there was a half-century-long series of semi-manual studies of centromere architecture, a rigorous centromere annotation algorithm is still lacking. Moreover, an automated centromere annotation is a prerequisite for studies of genetic diseases associated with centromeres, and evolutionary studies of centromeres across multiple species. Although the monomer decomposition (transforming a centromere into a monocentromere written in the monomer alphabet) and the HOR decomposition (representing a monocentromere in the alphabet of HORs) are currently viewed as two separate problems, we demonstrate that they should be integrated into a single framework in such a way that HOR (monomer) inference affects monomer (HOR) inference. We thus developed the HORmon algorithm that integrates the monomer/HOR inference and automatically generates the human monomers/HORs that are largely consistent with the previous semi-manual inference.

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A Game of Thrones at Human Centromeres I. Multifarious structure necessitates a new molecular/evolutionary model

Cited by 14 publications

References 102 publications

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

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

Centromeric repeats of the Western European house mouse I: high sequence diversity among monomers at local and global spatial scales

HORmon: automated annotation of human centromeres

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