Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

By J. R. Lupski, Pawel Stankiewicz. PLoS Genetics, 2005

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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.

Subfields: Genetics, Plant Science

View Paper: https://www.semanticscholar.org/paper/9c808f977d3e04745625b741371bf37457874520

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Citations in the corpus

High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. (2009, background): “…(CNV) in the human genome significantly influences human diversity and predisposition to disease (Sebat et al. 2004, 2007; Sharp et al. 2005; Conrad et al. 2006; Feuk et al. 2006; Hinds et al. 2006; McCarroll et al. 2006; Redon et al. 2006; Kidd et al. 2008; Perry et al. 2008; Walsh et al. 2008).”
Copy-number variations associated with neuropsychiatric conditions (2008, background): “Alternatively, CNVs may disrupt a regulatory element, generate novel fusion products, or act by way of position effect, with various possible positive and negative sequelae, including imprinting and differential allelic expressio”
Annotating non-coding regions of the genome (2010, background): “Copy-number variants that contain genes often have their origin in recombination between non-coding repeat region”
A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation (2009, background): “At the same time MMBIR could create LCRs that provides the homology required for NAHR, leading to genomic disorders in future generations.”
Copy number variation: new insights in genome diversity. (2006, background): “same chromosome or on different, nonhomologous chromosomes (Bailey et al. 2002; Lupski and Stankiewicz 2005).”
A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. (2007, background): “Genomic disorders are a group of human genetic diseases caused by DNA rearrangements that result in the gain, loss, or disruption of a gene(s) for which dosage is critical Cell 1 (Lupski, 1998; Lupski and Stankiewicz, 2005, 2006).”
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. (2009, background): “…together with awareness that the human genome map continues to evolve toward a more complete reference sequence with consequent repositioning of genes and other elements, need to be considered 32,33 because they necessarily imply a degree of caution in interpreting and using data in DECIPHER.”
Mechanisms for human genomic rearrangements (2008, background): “The pathological conditions caused by genomic rearrangements are collectively defined as genomic disorders [1-3].”