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Mechanisms for Structural Variation in the Human Genome
#MMPMID23730541
Currall BB
; Chiang C
; Talkowski ME
; Morton CC
Curr Genet Med Rep
2013[Jun]; 1
(2
): 81-90
PMID23730541
show ga
It has been known for several decades that genetic variation involving changes to
chromosomal structure (i.e., structural variants) can contribute to disease;
however this relationship has been brought into acute focus in recent years
largely based on innovative new genomics approaches and technology. Structural
variants (SVs) arise from improperly repaired DNA double-strand breaks (DSB).
DSBs are a frequent occurrence in all cells and two major pathways are involved
in their repair: homologous recombination and non-homologous end joining. Errors
during these repair mechanisms can result in SVs that involve losses, gains and
rearrangements ranging from a few nucleotides to entire chromosomal arms. Factors
such as rearrangements, hotspots and induced DSBs are implicated in the formation
of SVs. While de novo SVs are often associated with disease, some SVs are
conserved within human subpopulations and may have had a meaningful influence on
primate evolution. As the ability to sequence the whole human genome rapidly
evolves, the diversity of SVs is illuminated, including very complex
rearrangements involving multiple DSBs in a process recently designated as
"chromothripsis". Elucidating mechanisms involved in the etiology of SVs informs
disease pathogenesis as well as the dynamic function associated with the biology
and evolution of human genomes.
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