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Functional epialleles at an endogenous human centromere.

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Date
2012-08-21
Authors
Maloney, Kristin A
Sullivan, Lori L
Matheny, Justyne E
Strome, Erin D
Merrett, Stephanie L
Ferris, Alyssa
Sullivan, Beth A
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Abstract
Human centromeres are defined by megabases of homogenous alpha-satellite DNA arrays that are packaged into specialized chromatin marked by the centromeric histone variant, centromeric protein A (CENP-A). Although most human chromosomes have a single higher-order repeat (HOR) array of alpha satellites, several chromosomes have more than one HOR array. Homo sapiens chromosome 17 (HSA17) has two juxtaposed HOR arrays, D17Z1 and D17Z1-B. Only D17Z1 has been linked to CENP-A chromatin assembly. Here, we use human artificial chromosome assembly assays to show that both D17Z1 and D17Z1-B can support de novo centromere assembly independently. We extend these in vitro studies and demonstrate, using immunostaining and chromatin analyses, that in human cells the centromere can be assembled at D17Z1 or D17Z1-B. Intriguingly, some humans are functional heterozygotes, meaning that CENP-A is located at a different HOR array on the two HSA17 homologs. The site of CENP-A assembly on HSA17 is stable and is transmitted through meiosis, as evidenced by inheritance of CENP-A location through multigenerational families. Differences in histone modifications are not linked clearly with active and inactive D17Z1 and D17Z1-B arrays; however, we detect a correlation between the presence of variant repeat units of D17Z1 and CENP-A assembly at the opposite array, D17Z1-B. Our studies reveal the presence of centromeric epialleles on an endogenous human chromosome and suggest genomic complexities underlying the mechanisms that determine centromere identity in humans.
Type
Journal article
Subject
Alleles
Animals
Autoantigens
Centromere
Centromere Protein B
Chromatin
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
Chromosomes
Heterochromatin
Heterozygote
Humans
Kinetochores
Meiosis
Mice
Polymorphism, Genetic
Permalink
https://hdl.handle.net/10161/12802
Published Version (Please cite this version)
10.1073/pnas.1203126109
Publication Info
Maloney, Kristin A; Sullivan, Lori L; Matheny, Justyne E; Strome, Erin D; Merrett, Stephanie L; Ferris, Alyssa; & Sullivan, Beth A (2012). Functional epialleles at an endogenous human centromere. Proc Natl Acad Sci U S A, 109(34). pp. 13704-13709. 10.1073/pnas.1203126109. Retrieved from https://hdl.handle.net/10161/12802.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Sullivan

Beth Ann Sullivan

James B. Duke Distinguished Professor
Research in the Sullivan Lab is focused on chromosome organization, with a specific emphasis on the genomics and epigenetics of the chromosomal locus called the centromere. The centromere is a specialized chromosomal site involved in chromosome architecture and movement, and when defective, is linked to cancer, birth defects, and infertility. The lab has described a unique type of chromatin (CEN chromatin) that forms exclusively at the centromere by replacement of core histone H3 by the centrome
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