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Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

By James R Lupski and Pawel Stankiewicz


Rearrangements of our genome can be responsible for inherited as well as sporadic traits. The analyses of chromosome breakpoints in the proximal short arm of Chromosome 17 (17p) reveal nonallelic homologous recombination (NAHR) as a major mechanism for recurrent rearrangements whereas nonhomologous end-joining (NHEJ) can be responsible for many of the nonrecurrent rearrangements. Genome architectural features consisting of low-copy repeats (LCRs), or segmental duplications, can stimulate and mediate NAHR, and there are hotspots for the crossovers within the LCRs. Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes. Genomic rearrangements may cause Mendelian diseases, produce complex traits such as behaviors, or represent benign polymorphic changes. The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, gene interruption, generation of a fusion gene, position effects, unmasking of recessive coding region mutations (single nucleotide polymorphisms, SNPs, in coding DNA) or other functional SNPs, and perhaps by effects on transvection

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