Elucidation of the Structure of Inverted Duplications: Heterogeneity in the Mechanism of Formation. A.E. Murmann¹, C.A. Curtis², L.A. Christ², D.F. Conrad¹, H. Mashek¹, S. Schwartz¹. 1) Human Genetics, University of Chicago, Chicago, IL; 2) Case Western Reserve University, Cleveland, OH.
   The development of molecular technologies in cytogenetics has lead to a better understanding of the mechanism of the formation of a variety of chromosomal abnormalities. Inverted duplications (inv dup), although rare, comprise approximately 13% of all intrachromosomal rearrangements and broadly fall into four categories: inv dup; inv dup with concomitant deletion; accessory acentric inv dup (acentric inv dup); and accessory dicentric inv dup. We have acertained 12 different inv dups (most with a concomitant deletion) and an additional 14 acentric inv dups and have completed precise breakpoint analysis in 9 and 5 of these cases, respectively, using FISH analysis, qRT-PCR, and quantitative SNP-microarray analysis. These analyses were performed to determine if the same mechanism is involved in the formation of one category of inv dups or even shared between different categories. This study demonstrates a number of very intriguing findings regarding the mechanisms of formation on these inv dups: (1) There is no specific mechanism of formation leading to the different types of inv dups; (2) We found heterogeneity of the breakpoints localized to both chromosomes 13 and 15; (3) None of the five acentric inv dups were associated with the presence of low copy repeats (LCR); (4) The formation of one acentric inv dup of chromosome 9 was highly unique in that it did not start at the breakpoint on chromosome 9; but rather involved a deletion of material; (5) Four of the nine inv dups with deletion involved the fusion of two chromosomal segments that were nonsymmetrical leaving a deletion, a stretch of single copy material followed by the duplication; (6) Four of the inv dups were associated with LCR elements; however these were very chromosome specific (one on chromosome 22 and three on chromosome 8); (7) All three chromosome 8p abnormalities involved the same breakpoint; and (8) All 5 analyzed breakpoint regions of acentric inv dups coincided within regions of evolutionary breakpoints, as did half of the analyzed breakpoints of the other inv dups.