Transposable genetic elements (TEs) occupy 44% of the human genome. Human TEs such as the L1 element can cause diseases when they """"""""jump"""""""" into genes, and several dozen disease-causing TE insertions have been documented in humans. It has been widely assumed that TE mobilization occurs primarily in the human germline. However, several recent lines of evidence indicate that the human L1 element also transposes in somatic cells. Somatic L1 insertions have been observed in at least two types of human tumors, suggesting that such insertions may produce disease states, including cancers. In this proposal, we will examine the relative levels of germline vs. somatic L1 mobilization in humans.
In Aim 1, we will use our recently developed transposon-seq technologies to examine L1 insertions in a tissue panel obtained from healthy Americans. By studying L1 mobilization in multiple tissues from the same individuals, we will establish the relative abundances of germline vs. somatic L1 insertions in healthy Americans. We also will seek evidence for the RNA carryover mechanism of L1 mobilization, which produces mosaic somatic insertions in mice and may also produce such insertions in humans.
In Aim 2, we will examine normal/tumor tissue pairs to determine whether germline and somatic L1 insertions help to drive tumor formation in humans. Our laboratory recently found that L1 is mobilized at high frequencies in human lung tumors, and we suspect that some of the new L1 insertions fuel tumorigenesis. We will directly test this hypothesis in Aim 2. We also will determine whether somatic L1 mobilization occurs in other tumor types.
In Aim 3, we will study source elements that produce new L1 insertions in humans. We will determine whether source element copy number influences L1 mutagenesis and cancer risk in humans. Finally, we will test the hypothesis that source elements are controlled by methylation in human lung cancers. Together, these studies will greatly expand our knowledge of L1 mutagenesis in humans and will provide major new insights on how L1 mutagenesis impacts human health.
Project Narrative In this project, we build upon several recent studies from our laboratory to more fully understand the impact of transposable genetic elements on human health. Transposable elements are small segments of DNA that can move from one site to another in genomes. Our laboratory is studying naturally-occurring transposable elements in the human genome. These elements are endogenous mutagens that can cause genomic damage. For example, when they move into genes, transposable elements can mutate the genetic information that is stored there, which, in turn, can produce human diseases. Thus, our studies of human transposable elements are relevant to the broad mission of the NIH. Our studies will provide a better understanding of how transposable elements cause human diseases, including cancers.
|Scott, Emma C; Gardner, Eugene J; Masood, Ashiq et al. (2016) A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res 26:745-55|
|Nugent, Bridget M; Wright, Christopher L; Shetty, Amol C et al. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690-7|
|Szymanski, Eva P; Leung, Janice M; Fowler, Cedar J et al. (2015) Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med 192:618-28|
|1000 Genomes Project Consortium; Auton, Adam; Brooks, Lisa D et al. (2015) A global reference for human genetic variation. Nature 526:68-74|
|Sudmant, Peter H; Rausch, Tobias; Gardner, Eugene J et al. (2015) An integrated map of structural variation in 2,504 human genomes. Nature 526:75-81|
|Delaneau, Olivier; Marchini, Jonathan; 1000 Genomes Project Consortium et al. (2014) Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel. Nat Commun 5:3934|
|Colonna, Vincenza; Ayub, Qasim; Chen, Yuan et al. (2014) Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences. Genome Biol 15:R88|
|Khurana, Ekta; Fu, Yao; Colonna, Vincenza et al. (2013) Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 342:1235587|
|1000 Genomes Project Consortium; Abecasis, Goncalo R; Auton, Adam et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56-65|