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

• Published in: Nature genetics Vol. 43; no. 11; pp. 1074 - 1081
• Main Authors: Carvalho, Claudia M B, Ramocki, Melissa B, Pehlivan, Davut, Franco, Luis M, Gonzaga-Jauregui, Claudia, Fang, Ping, McCall, Alanna, Pivnick, Eniko Karman, Hines-Dowell, Stacy, Seaver, Laurie H, Friehling, Linda, Lee, Sansan, Smith, Rosemarie, del Gaudio, Daniela, Withers, Marjorie, Liu, Pengfei, Cheung, Sau Wai, Belmont, John W, Zoghbi, Huda Y, Hastings, P J, Lupski, James R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/2489/144; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Diverse techniques; Fundamental and applied biological sciences. Psychology; Gene Function; Gene Rearrangement; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomes; Genomics; Genotype & phenotype; Haplotypes; Human Genetics; Human genome; Humans; Methyl-CpG-Binding Protein 2 - genetics; Molecular and cellular biology; Phenotype; Polymorphism, Single Nucleotide; Repetitive Sequences, Nucleic Acid; Studies; Human; Genome; Inverted repeated sequence; Genomics
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.944

Jim Lupski and colleagues report characterization of complex genomic rearrangements at the MECP2 and PLP1 loci. They show that all the complex rearrangement products share a common genomic organization wherein the triplicated segment is inverted and located between directly oriented duplicated genomic segments; these structures are mediated by inverted repeats that can be separated by over 300 kb. 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.