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Formation of novel CENP-A domains on tandem repetitive DNA and across chromosome breakpoints on human chromosome 8q21 neocentromeres

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Abstract

Endogenous human centromeres form on megabase-sized arrays of tandemly repeated alpha satellite DNA. Human neocentromeres form epigenetically at ectopic sites devoid of alpha satellite DNA and permit analysis of centromeric DNA and chromatin organization. In this study, we present molecular cytogenetic and CENP-A chromatin immunoprecipitation (ChIP) on CHIP analyses of two neocentromeres that have formed in chromosome band 8q21 each with a unique DNA and CENP-A chromatin configuration. The first neocentromere was found on a neodicentric chromosome 8 with an inactivated endogenous centromere, where the centromeric activity and CENP-A domain were repositioned to band 8q21 on a large tandemly repeated DNA. This is the first example of a neocentromere forming on repetitive DNA, as all other mapped neocentromeres have formed on single copy DNA. Quantitative fluorescent in situ hybridization (FISH) analysis showed a 60% reduction in the alpha satellite array size at the inactive centromere compared to the active centromere on the normal chromosome 8. This neodicentric chromosome may provide insight into centromere inactivation and the role of tandem DNA in centromere structure. The second neocentromere was found on a neocentric ring chromosome that contained the 8q21 tandemly repeated DNA, although the neocentromere was localized to a different genomic region. Interestingly, this neocentromere is composed of two distinct CENP-A domains in bands 8q21 and 8q24, which are brought into closer proximity on the ring chromosome. This neocentromere suggests that chromosomal rearrangement and DNA breakage may be involved in neocentromere formation. These novel examples provide insight into the formation and structure of human neocentromeres.

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Acknowledgments

PEW would like to acknowledge Jacob Glass and Mathilde Etcheverry for preliminary studies and Manisha Bramachary and Omar Jabado for statistical advice. JJME would like to acknowledge Jozefa van Lent-Albrechts and Nienke Muntjewerff for technical assistance. The authors acknowledge the Mount Sinai qPCR Shared Resource Facility and the Mount Sinai Microarray, PCR, and Bioinformatics Shared Research Facility. PEW was funded by NIH grant R01 GM061150.

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, Box 1498, 1425 Madison Ave, Icahn Medical Institute 14-20E, New York, NY, 10029, USA

    Dan Hasson, Alicia Alonso, Fanny Cheung & Peter E. Warburton

  2. The Mount Sinai Graduate School of Biological Sciences, New York, NY, USA

    Dan Hasson & Peter E. Warburton

  3. Laboratory Corporation of America, Research Triangle Park, NC, USA

    James H. Tepperberg & Peter R. Papenhausen

  4. Department of Clinical Genetics, Academic Hospital Maastricht, Maastricht, the Netherlands

    John J. M. Engelen

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  1. Dan Hasson
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  2. Alicia Alonso
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  3. Fanny Cheung
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  4. James H. Tepperberg
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  5. Peter R. Papenhausen
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  6. John J. M. Engelen
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  7. Peter E. Warburton
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Correspondence to Peter E. Warburton.

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Communicated by Andy Choo

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Hasson, D., Alonso, A., Cheung, F. et al. Formation of novel CENP-A domains on tandem repetitive DNA and across chromosome breakpoints on human chromosome 8q21 neocentromeres. Chromosoma 120, 621–632 (2011). https://doi.org/10.1007/s00412-011-0337-6

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