We recently proposed a DNA replication–based mechanism of fork stalling and template switching (FoSTeS) to explain the complex genomic rearrangements associated with a dysmyelinating central nervous system disorder in humans1. The FoSTeS mechanism has been further generalized and molecular mechanistic details have been provided in the microhomology-mediated break-induced replication (MMBIR) model that may underlie many structural variations in genomes from all domains of life2. Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR. Furthermore, we show that FoSTeS/MMBIR-mediated rearrangements can occur mitotically and can result in duplication or triplication of individual genes or even rearrangements of single exons. The FoSTeS/MMBIR mechanism can explain both the gene duplication-divergence hypothesis3 and exon shuffling4, suggesting an important role in both genome and single-gene evolution.
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We thank all participating subjects and families for their kind cooperation in the study. We also thank W. Bi, W. Gu, J.A. Lee and P. Stankiewicz for their critical reviews and C.M.B. Carvalho and M.A. Withers for their assistance. This work was supported in part by the Charcot Marie Tooth Association and the National Institute of Neurological Disorders and Stroke (NINDS, NIH).
J.R.L. is a consultant for Athena Diagnostics, 23andMe and Ion Torrent Systems Inc., and holds multiple US and European patents for DNA diagnostics. Furthermore, the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular diagnostic testing (MGL, http://www.bcm.edu/geneticlabs/).
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2018 Victor A. McKusick Leadership Award: Molecular Mechanisms for Genomic and Chromosomal Rearrangements
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