Functional epialleles at an endogenous human centromere

Maloney, Kristin A.; Sullivan, Lori L.; Matheny, Justyne E.; Strome, Erin D.; Merrett, Stephanie L.; Ferris, Alyssa C.; Sullivan, Beth A.

doi:10.1073/pnas.1203126109

Cited by 71 publications

(105 citation statements)

References 37 publications

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“…Human artificial chromosomes were identified for five of the six higherorder repeat constructs tested (Table 1). In the cases of DXZ1 and D17Z1B, our data are consistent with previous reports (7,(43)(44)(45). The one higher-order repeat construct that did not support formation of human artificial chromosomes was a construct containing D19Z1 alpha satellite, which, perhaps notably, contains the lowest CENP-B box density with the most varied motif periodicity among the alpha satellite arrays tested here.…”

Section: Assessment Of Alpha Satellite Sequence Variation In An Indivsupporting

confidence: 82%

Sequences Associated with Centromere Competency in the Human Genome

Hayden

Strome

Merrett

et al. 2013

Molecular and Cellular Biology

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124

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Centromeres, the sites of spindle attachment during mitosis and meiosis, are located in specific positions in the human genome, normally coincident with diverse subsets of alpha satellite DNA. While there is strong evidence supporting the association of some subfamilies of alpha satellite with centromere function, the basis for establishing whether a given alpha satellite sequence is or is not designated a functional centromere is unknown, and attempts to understand the role of particular sequence features in establishing centromere identity have been limited by the near identity and repetitive nature of satellite sequences. Utilizing a broadly applicable experimental approach to test sequence competency for centromere specification, we have carried out a genomic and epigenetic functional analysis of endogenous human centromere sequences available in the current human genome assembly. The data support a model in which functionally competent sequences confer an opportunity for centromere specification, integrating genomic and epigenetic signals and promoting the concept of context-dependent centromere inheritance.

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Section: Assessment Of Alpha Satellite Sequence Variation In An Indivsupporting

confidence: 82%

Sequences Associated with Centromere Competency in the Human Genome

Hayden

Strome

Merrett

et al. 2013

Molecular and Cellular Biology

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124

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“…We used CENPA immunostaining and CENPA ChIP-PCR to assign the location of centromere assembly, so that each HSA17 in our data set was functionally characterized before proceeding to the analysis of molecular variation (Table 1; Supplemental Fig. S1; Maloney et al 2012). Our data from previously published studies suggested that variation within the HORs of D17Z1 arrays could be linked to centromere location on HSA17 (Maloney et al 2012).…”

Section: D17z1 Hor Sequence Variation Is Associated With Metastable Cmentioning

confidence: 84%

“…There is little contiguous sequence information between D17Z1-B/D17Z1 and D17Z1/ D17Z1-C; however, BAC end sequencing supports that the arrays are essentially adjacent (Rudd et al 2006). In previous studies, we demonstrated that the functional centromere on HSA17 is assembled at either D17Z1 or D17Z1-B (Maloney et al 2012). We showed that in ∼70% of individuals studied, the centromere is assembled at D17Z1, while in 30% of individuals, the centromere is assembled at D17Z1 on one homolog and at D17Z1-B on the other HSA17 homolog.…”

mentioning

confidence: 99%

“…The frequency of individuals that have HSA17s in which the centromere assembles at D17Z1-B and the proportion of HSA17s that contain variant HORS (indel and SNP) are remarkably similar (∼30%) (Warburton and Willard 1995;Maloney et al 2012). We hypothesized based on our previous studies that D17Z1 variation might influence centromere location and function.…”

mentioning

confidence: 99%

“…To date, no individuals have been identified that exhibit centromere assembly at D17Z1-B on both HSA17 homologs. D17Z1-B can robustly support centromere assembly in human artificial chromosome (HAC) assays (Maloney et al 2012;Hayden et al 2013); therefore, it is possible that D17Z1-B/ D17Z1-B homozygous centromeres represent rare alleles that may only be identified by deeper screening of the population. The molecular basis of these HSA17 centromeric epialleles and (epi)genomic features that direct their assembly are unknown.…”

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confidence: 99%

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Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles

et al. 2016

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Alpha satellite is a tandemly organized type of repetitive DNA that comprises 5% of the genome and is found at all human centromeres. A defined number of 171-bp monomers are organized into chromosome-specific higher-order repeats (HORs) that are reiterated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. We previously showed that the two alpha satellite arrays of Homo sapiens Chromosome 17 (HSA17), D17Z1 and D17Z1-B, behave as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, can form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other. In this study, we aimed to understand the molecular basis for how centromere location is determined on HSA17. Specifically, we focused on D17Z1 genomic variation as a driver of epiallele formation. We found that D17Z1 arrays that are predominantly composed of HOR size and sequence variants were functionally less competent. They either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable. Our study demonstrates that genomic variation within highly repetitive, noncoding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.

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The Evolution of CentromericDNASequences

Brown

O’Neill

2014

Encyclopedia of Life Sciences

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For most eukaryotic species, the centromere is comprised of millions of base pairs of tandemly repeated deoxyribonucleic acid (DNA) sequences. Centromere function is broadly conserved across eukaryotic phyla, yet centromere DNA presents several unique conundrums for biologists, further complicated by the challenges in studying highly repeated regions of complex genomes. Contrary to the expectation that centromeric sequences would be constrained to maintain centromere function across species, these sequences are among the most rapidly evolving sequences in any given genome. This discordance between functional constraint and sequence divergence, termed the ‘centromere paradox’, appears to defy basic laws of Mendelian inheritance. Multiple genetic mechanisms have been proposed to explain centromeric DNA complexity and rapid evolutionary divergence, taking into consideration the unique chromosome architecture and dynamics of the centromere during both mitosis and meiosis. Stochastic processes affecting sequence evolution and the selective constraint necessary for centromere protein recognition are balanced in an ongoing conflict that ultimately manifests as rapid centromere DNA evolution. Key Concepts: Loss of centromere function does not equate to loss of centromere sequence. Conversely, centromere sequences do not strictly demarcate a functional centromere. The constitution of centromeric satellite DNAs across species differs not only in sequence, but also in the repeat unit length, abundance of the repeat unit and the complexity of the genomic structure of multiple repeat units. The more commonly found regional centromere is typified by a distinct, linear organisation of a given satellite repeat unit into high‐copy tandem repeats of that unit than can span megabases of DNA. The high homology of the higher‐order satellite repeats within a centromere is consistent with their function to effectively bind centromere proteins, wherein selection may favour homogeneity to retain centromere function. Initial forms of an active centromere do not necessarily require HOR satellite arrays, but rather such arrays evolve over evolutionary timescales following stable establishment and inheritance of a new centromere. The process of molecular drive, involving concerted evolution and gene conversion results in the homogenisation and fixation of a given repeat variant and may lead to the convergent and concerted evolution of satellites within one species. Genetic conflict and/or meiotic drive may be responsible for the different centromere satellite sequence suites found between species. Centromere Drive may be responsible for the rapid divergence of functional centromeric sequences between species. The coding sequences for two centromere proteins, CENP‐A (centromere‐specific histone H3) and CENP‐C (a centromere‐specific DNA binding protein), evolve at rates faster than expected for either neutral (unconstrained) or purifying (selectively constrained) evolution in many species. Mobile elements can impact the rate at which satellites are derived, expand, contract and homogenise within a species.

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Functional epialleles at an endogenous human centromere

Cited by 71 publications

References 37 publications

Sequences Associated with Centromere Competency in the Human Genome

Sequences Associated with Centromere Competency in the Human Genome

Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles

The Evolution of CentromericDNASequences

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