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Human Molecular Genetics Advance Access published online on March 31, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp160
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Inverted Duplications on Acentric Markers: Mechanism of Formation

Andrea E. Murmann1,*, Donald F. Conrad1, Heather Mashek1, Chris A. Curtis2, Raluca I. Nicolae1, Carole Ober1 and Stuart Schwartz1

1 Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA 2 Case Western Reserve University, Cleveland, OH 44106, USA

* Corresponding Author: Andrea Murmann, Department of Human Genetics, University of Chicago, 5841 S. Maryland Ave., Room L-155, MC0077, Chicago, IL 60637, USA, Tel: +1 773 834 0555, Fax: +1 773 834 0556, Email: amurmann{at}uchicago.edu

Received December 17, 2008; Revised March 26, 2009; Accepted March 26, 2009

Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found both in patients with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (3 trisomic, 6 tetrasomic, 2 polysomic, and 1 X chromosome derived marker) using a combination of fluorescence in situ hybridization (FISH), quantitative SNP-array, and microsatellite analysis. Inv dup markers were found to form either symmetrically with 1 breakpoint or asymmetrically with 2 distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. Based on the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: Following a double strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker's survival during cell division and its presence in all cells.


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