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“Genomic disorders are common diseases: studying copy-number variation (CNV) to understand
human development and disease.”
Name: James R. Lupski, Institution: Baylor College of Medicine, Houston, Texas, U.S.A.
Whereas Watson-Crick DNA base pair changes have long been recognized as a mechanism for
mutations, rearrangements of the human genome including deletions, duplications, and inversions have
been appreciated only more recently as a significant source for human genetic variation. Diseases that
result from DNA rearrangements have been referred to as genomic disorders. Structural variation of our
genome can be responsible for inherited as well as sporadic traits. Rearrangements associated with
genomic disorders can be recurrent, with breakpoint clusters resulting in a common sized
deletion/duplication, or nonrecurrent and of different sizes. The analyses of 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 non-recurrent rearrangements. Genome architectural features consisting of
low-copy repeats (LCRs), also called segmental duplications, can stimulate and mediate NAHR. There
are positional hotspots for the crossovers within the LCRs. We recently elucidated a DNA replication
mechanism for nonrecurrent rearrangements that we termed FoSTeS – Fork Stalling and Template
Switching. A newer model, microhomology-mediated break-induced replication or MMBIR, provides
further molecular mechanistic details and may be operative in all life forms as a means to process oneended, double-stranded DNA generated by collapsed forks. 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 and complex traits such as obesity
and neurobehavioral phenotypes. The mechanisms by which rearrangements convey phenotypes are
diverse and include gene dosage, position effects, unmasking of coding region mutations (cSNPs) or
other functional SNPs, creating gain-of-function fusion genes at the breakpoints, and perhaps through
effects of transvection. De novo genomic rearrangements have been shown to cause both chromosomal
and Mendelian disease, as well as sporadic traits, but our understanding of the extent to which genomic
rearrangements, gene CNV, and/or gene dosage alterations are responsible for common and complex
traits remains rudimentary.
1. Lupski, J.R. (2007). Genomic rearrangements and sporadic disease. Nature Genetics 39:S43-S47.
2. Lee, J., Carvalho, C.M.B., Lupski, J.R. (2007). A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235-1247.
3. Carvalho, C.M., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C., Peacock, S., Shaw, C., Pursley,
A., Tavyev, J., Ramocki, M., Nawara, M., Obersztyn, E., Vianna-Morgante, A.M., Zoghbi, H.,
Cheung, S.W., and Lupski, J.R. (2009). Complex rearrangements in MECP2 duplicated patients
suggest Fork Stalling and Template Switching (FoSTeS) as a major mechanism. Hum. Mol.
Genet. 18:2188-2203.
4. Zhang, F., Khajavi, M., Connolly, A., Towne, C.F., Batish, S.V., Lupski, J.R. (2009). The DNA
replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exonic
complex rearrangements. Nature Genetics 41:849-853.
5. Zhang, F., Carvalho, C.M.B., Lupski, J.R. (2009). Complex human chromosomal and genomic
rearrangements. Trends in Genetics 25:298-307.
6. Lupski, J.R. (2009). Genomic disorders ten years on. Genome Medicine 1:42.
7. Hastings, P.J., Lupski, J.R., Rosenberg, S.M., Ira, G. (2009). Mechanisms of change in gene copy number.
Nature Reviews Genetics 10:551-564.