Functional epialleles at an endogenous human centromere.
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2012-08-21
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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.
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Maloney, Kristin A, Lori L Sullivan, Justyne E Matheny, Erin D Strome, Stephanie L Merrett, Alyssa Ferris and Beth A Sullivan (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.
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Lori Sullivan
I serve as Lab Manager and research technician in the Sullivan lab, where we study the structural dynamics, stability, and function of human chromosomes, with particular interest in the chromosomal locus known as the centromere.
Our focused studies contribute to a greater understanding of chromosome instability and inheritance associated with reproductive abnormalities, birth defects, and cancer.
Beth Ann Sullivan
Beth Sullivan is the Vice Dean for Basic and Preclinical Science in the School of Medicine. In this role, she provides strategic leadership for the School of Medicine’s basic and preclinical science enterprise. She oversees planning and alignment across basic science departments, research centers, and institutes and work with clinical and administrative leaders to strengthen the school’s research portfolio, support faculty recruitment and development, and ensure that the school’s infrastructure, training programs, and resources position Duke at the forefront of discovery. She is also a James B. Duke Professor of Molecular Genetics and Microbiology, overseeing a research program that studies the genetics and genomics of human chromosome inheritance.
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