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Unformatted text preview: Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease Christine J. Shaw 1 and James R. Lupski 1,2,3, * 1 Department of Molecular and Human Genetics and 2 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA, and 3 Texas Childrens Hospital, Houston, Texas, USA Received December 19, 2003; Revised January 14, 2004; Accepted January 26, 2004 The term genomic disorder refers to a disease that is caused by an alteration of the genome that results in complete loss, gain or disruption of the structural integrity of a dosage sensitive gene(s). In most of the common chromosome deletion/duplication syndromes, the rearranged genomic segments are anked by large (usually > 10kb), highly homologous low copy repeat (LCR) structures that can act as recombination substrates. Recombination between non-allelic LCR copies, also known as non-allelic homologous recombination, can result in deletion or duplication of the intervening segment. Recent findings suggest that other chromosomal rearrangements, including reciprocal, Robertsonian and jumping translocations, inversions, isochromosomes and small marker chromosomes, may also involve susceptibility to rearrangement related to genome structure or architecture. In several cases, LCRs, AT-rich palindromes and pericentromeric repeats are located at such rearrangement breakpoints. Analysis of the products of recombination at the junctions of the rearrangements reveals both homologous recombination and non- homologous end joining as causative mechanisms. Thus, a more global concept of genomic disorders emerges in which susceptibility to rearrangements occurs due to underlying complex genomic architecture. Interestingly, this architecture plays a role not only in disease etiology, but also in primate genome evolution. In this review, we discuss recent advances regarding general mechanisms for the various rearrangements of our genome, and potential models for rearrangements with non-homologous breakpoint regions. INTRODUCTION Genomic disorders previously have been defined as disorders in which the clinical phenotype is a consequence of abnormal dosage of a gene(s) located within a rearranged segment of the genome (13). This group of disorders is distinguished from conventional Mendelian disease in that the phenotype does not result from a point mutation, but rather from larger alterations of the genome. These alterations include deletions, duplica- tions, inversions and translocations. Such rearrangements occur via recombination mechanisms whereas point mutations usually result from DNA replication or repair errors. The number of recognized genomic disorders continues to expand, with the recent additions of Sotos syndrome (SoS), split hand split foot malformation 3 (SHFM3), and Kabuki syndrome (KS) (46)....
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- Spring '05