Mechanisms for Structural Variation in the Human Genome.

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.