Letter abstract

Nature Genetics 41, 849 - 853 (2009)
Published online: 21 June 2009 | doi:10.1038/ng.399

The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans

Feng Zhang1, Mehrdad Khajavi1, Anne M Connolly2, Charles F Towne3, Sat Dev Batish3 & James R Lupski1,4,5


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.

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  2. Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
  3. Athena Diagnostics, Inc., Worcester, Massachusetts, USA.
  4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  5. Texas Children's Hospital, Houston, Texas, USA.

Correspondence to: James R Lupski1,4,5 e-mail: jlupski@bcm.tmc.edu


These links to content published by NPG are automatically generated.


Copy number variation and human genome maps

Nature Genetics News and Views (01 May 2010)