Functional epialleles at an endogenous human centromere.
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 articleSubject
AllelesAnimals
Autoantigens
Centromere
Centromere Protein B
Chromatin
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
Chromosomes
Heterochromatin
Heterozygote
Humans
Kinetochores
Meiosis
Mice
Polymorphism, Genetic
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https://hdl.handle.net/10161/12802Published Version (Please cite this version)
10.1073/pnas.1203126109Publication 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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Show full item recordScholars@Duke
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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