Functional epialleles at an endogenous human centromere.

Maloney, Kristin A

Sullivan, Lori L

Matheny, Justyne E

Strome, Erin D

Merrett, Stephanie L

Ferris, Alyssa

Sullivan, Beth A

United States

2016-09-28T22:16:21Z

2012-08-21

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.

http://www.ncbi.nlm.nih.gov/pubmed/22847449

1203126109

1091-6490

https://hdl.handle.net/10161/12802

eng

Proceedings of the National Academy of Sciences

Proc Natl Acad Sci U S A

10.1073/pnas.1203126109

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

Functional epialleles at an endogenous human centromere.

Journal article

Sullivan, Beth A|0000-0001-5216-4603

http://www.ncbi.nlm.nih.gov/pubmed/22847449

13704

13709

34

Basic Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Molecular Genetics and Microbiology

School of Medicine

Published

109