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United States Department of Agriculture

Agricultural Research Service


Location: Children's Nutrition Research Center

Title: Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome)

item Carvalho, Claudia
item Ramocki, Melissa
item Pehlivan, Davut
item Franco, Luis
item Gonzaga-jauregui, Claudia
item Fang, Ping
item Mccall, Alanna
item Karman pivnick, Eniko
item Hines-dowell, Stacy
item Seaver, Laurie
item Friehling, Linda
item Lee, Sansan
item Smith, Rosemarie
item Del gaudio, Daniela
item Withers, Marjorie
item Liu, Pengfei
item Cheung, Sau wai
item Belmont, John
item Zoghbi, Huda
item Hastings, P
item Lupski, James

Submitted to: Nature Genetics
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/23/2011
Publication Date: 11/1/2011
Citation: Carvalho, C.M., Ramocki, M.B., Pehlivan, D., Franco, L.M., Gonzaga-Jauregui, C., Fang, P., McCall, A., Karman Pivnick, E., Hines-Dowell, S., Seaver, L.H., Friehling, L., Lee, S., Smith, R., Del Gaudio, D., Withers, M., Liu, P., Cheung, S., Belmont, J., Zoghbi, H.Y., Hastings, P.J., Lupski, J.R. 2011. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nature Genetics. 43(11):1074-1079.

Interpretive Summary: Some human genetic diseases are caused by duplications of the genetic material. This study shows for the first time that the duplications are often more complicated. These abnormalities consist of two duplicated segments of DNA flanking a triplicated center. Our contribution showed that the abnormality always occurs on one of the two chromosomes and does not involve sharing of genetic material between chromosomes. This study shows that there are characteristic structures – called inverted duplications - within particular parts of the genetic material that allow this to happen. They may affect a broader number of genetic diseases such as diabetes, cardiovascular disease, etc.

Technical Abstract: We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication(DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat–mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.

Last Modified: 8/24/2016
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