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posted 03. January 2006 10:08
PloS Genetics Research Review
Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes^
James R. Lupski, Pawel Stankiewicz
Introduction
Whereas Watson–Crick DNA base pair changes have long been recognized as a mechanism for mutation^, rearrangements of the human genome including deletions, duplications, and inversions have been appreciated only more recently as a significant source for genetic variation. Deletion and duplication mutations can vary in size from thousands to hundreds of thousands of base pairs in length and may require specialized technologies to visualize. Structural features, or the architecture, of the human genome can result in region-specific susceptibility to rearrangements and thus genomic instability. The molecular mechanisms by which rearrangement mutations of the human genome occur, and how such rearrangements convey phenotypes, are only beginning to be unraveled.
During the last decade it has become apparent that the molecular genetic mechanisms for many disease traits consist of genomic rearrangements rather than point mutations of single genes. Such conditions, in which the clinical phenotype is a consequence of abnormal dosage or dysregulation of one or more genes resulting from rearrangement of the genome, have been referred to as genomic disorders [1–4]. DNA^ rearrangements occur by both homologous and nonhomologous recombination mechanisms; however, homologous recombination (HR) appears to be the predominant pathway underlying recurrent rearrangements of our genome. Regardless of mechanism, structural features of the genome can predispose a particular region to rearrangement. Determining the architectural features that result in the instability of the genomic regions has profound consequences for clinical genetics as new technologies enable high-resolution analysis of the human genome. This review will focus on the information culled from, and molecular mechanisms elucidated by, breakpoint analyses of disease-associated rearrangements involving proximal 17p. Although the focus is 17p, such mechanisms appear to be generally applicable to all regions of the human genome. We also describe the many mechanisms by which rearrangements can convey phenotypes and discuss rearrangements as the basis for introducing variation in our genome.
Published: December 30, 2005
DOI: 10.1371/journal.pgen.0010049
Copyright: © 2005 Lupski and Stankiewicz. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Read full research review at PloS Genetics Research Review
[Emphases added by ISCID News Editor]
[Link-underlined terms with ^ indicate linked entry in ISCID Encyclopedia of Science and Philosophy as added by ISCID News Editor]
[ 05. January 2006, 19:00: Message edited by: ISCID News Editor ]
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