Abstract
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.
Highlights
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
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 [1,2,3,4]
It has been shown that the Charcot-Marie-Tooth disease type 1A (CMT1A) duplication and hereditary neuropathy with liability to pressure palsies (HNPP) deletion represent alternative products of a nonallelic homologous recombination (NAHR) utilizing CMT1A-REPs as recombination substrates [21,22]
Summary
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. The molecular mechanisms by which rearrangement mutations of the human genome occur, and how such rearrangements convey phenotypes, are only beginning to be unraveled.
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