Retrotransposons have had an important role in increasing repetition in the genome and have thereby had a major effect on evolutionary diversity. The retrotransposon L1 is a long interspersed nuclear element that pervades mammalian genomes in an enormous number of copies, most of which are truncated, rearranged, or otherwise mutated. In recent years, L1 insertions into genes have been found to cause disease in humans and mice. This application proposes to study the mechanism of L1 retrotransposition using a genetic approach, and to demonstrate a significant evolutionary function for active L1s, namely the ability to transduce DNA sequences to new genomic locations. Besides these studies, they will study site-specific retrotransposition in cultured cells by substitution or addition to L1 of endonuclease or DNA binding domains that have sequence specificity. In addition, they will study retrotransposition in vivo in transgenic mice, and use these mice to determine retrotransposition frequency in germ cell and somatic cell development. Lastly, they plan to initiate development of L1 elements into practical mutagenesis agents in mice.
| Doucet-O'Hare, Tara T; Sharma, Reema; Rodi?, Nemanja et al. (2016) Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma. Hum Mutat 37:942-54 |
| Hancks, Dustin C; Kazazian Jr, Haig H (2012) Active human retrotransposons: variation and disease. Curr Opin Genet Dev 22:191-203 |
| Hancks, Dustin C; Kazazian Jr, Haig H (2010) SVA retrotransposons: Evolution and genetic instability. Semin Cancer Biol 20:234-45 |
| Goodier, John L; Mandal, Prabhat K; Zhang, Lili et al. (2010) Discrete subcellular partitioning of human retrotransposon RNAs despite a common mechanism of genome insertion. Hum Mol Genet 19:1712-25 |
| Rangwala, Sanjida H; Kazazian Jr, Haig H (2009) The L1 retrotransposition assay: a retrospective and toolkit. Methods 49:219-26 |
| Goodier, John L; Zhang, Lili; Vetter, Melissa R et al. (2007) LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA-induced silencing complex. Mol Cell Biol 27:6469-83 |
| Kubo, Shuji; Seleme, Maria Del Carmen; Soifer, Harris S et al. (2006) L1 retrotransposition in nondividing and primary human somatic cells. Proc Natl Acad Sci U S A 103:8036-41 |
| Farley, Alexander H; Luning Prak, Eline T; Kazazian Jr, Haig H (2004) More active human L1 retrotransposons produce longer insertions. Nucleic Acids Res 32:502-10 |
| Deininger, Prescott L; Moran, John V; Batzer, Mark A et al. (2003) Mobile elements and mammalian genome evolution. Curr Opin Genet Dev 13:651-8 |
