Alu elements are primate-specific SINE mobile elements (Short, INterspersed Elements). They have amplified over the past 65 million years to the point where they occupy about 11% of the human genome, with well over 1 million copies per genome. They have been a major force in shaping the primate genome and whose insertion continues to cause approximately one in a thousand new human genetic diseases. In addition, once inserted, they continue to lead to mutations that affect gene splicing, triplet repeat diseases, and unequal Alu/Alu recombination, whiclvleads to a much higher level of disease. Studies on L1 elements are increasingly implicating human mobile elements in genetic damage to somatic cells. Thus, mobile elements are likely to represent one of the most important intrinsic factors contributing to genetic instability in both germ-line genetic disease, as well as somatic mutations leading to aging and diseases, such as cancer. Almost all current activity from Alu elements comes from a very small proportion of active elements. It is critical that we determine which features determine whether an Alu is active. This will allow us to determine whether some individuals are more prone to mobile element damage than others, or even suggest approaches to controlling that damage. We have also found that Alu elements can potentially be active under conditions where other human elements are not, making it important to characterize all of the major human mobile elements.
Our specific aims are: 1. To determine which aspects of the RNA produced by different Alu loci influence their relative activity in order to understand the approximately 4000-fold selection for activity by young Alu elements. We will specifically assess the role of A-tail length and heterogeneity, Alu subfamily mutations, as well as random mutations that might affect the RNA structure, and the 3'unique regions that will differ between different Alu loci. 2. To utilize new approaches to determine the diversity and levels of Alu RNA expression from different normal tissues. These studies will help us assess how many loci express in a given tissue and whether the loci differ between tissues. 3. We will utilize an approach that allows an assessment of specific aspects of Alu elements (such as transcription strength, A-tail length, mismatch, spacing etc.) to contribute to Alu/Alu unequal homologous recombination. These studies will help to shed light on the reasons why some genetic loci are particularly prone to this form of recombination and whether we can better predict regions of genetic instability in the genome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045668-17
Application #
7754112
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
1993-05-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
17
Fiscal Year
2010
Total Cost
$301,474
Indirect Cost
Name
Tulane University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Servant, Geraldine; Streva, Vincent A; Deininger, Prescott L (2017) Transcription coupled repair and biased insertion of human retrotransposon L1 in transcribed genes. Mob DNA 8:18
Servant, Geraldine; Streva, Vincent A; Derbes, Rebecca S et al. (2017) The Nucleotide Excision Repair Pathway Limits L1 Retrotransposition. Genetics 205:139-153
Morales, Maria E; Derbes, Rebecca S; Ade, Catherine M et al. (2016) Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes. PLoS One 11:e0151367
Morales, Maria E; White, Travis B; Streva, Vincent A et al. (2015) The contribution of alu elements to mutagenic DNA double-strand break repair. PLoS Genet 11:e1005016
Streva, Vincent A; Jordan, Vallmer E; Linker, Sara et al. (2015) Sequencing, identification and mapping of primed L1 elements (SIMPLE) reveals significant variation in full length L1 elements between individuals. BMC Genomics 16:220
Servant, Geraldine; Deininger, Prescott L (2015) Insertion of Retrotransposons at Chromosome Ends: Adaptive Response to Chromosome Maintenance. Front Genet 6:358
White, Travis B; McCoy, Adam M; Streva, Vincent A et al. (2014) A droplet digital PCR detection method for rare L1 insertions in tumors. Mob DNA 5:30
Wallace, Nicholas A; Gasior, Stephen L; Faber, Zachary J et al. (2013) HPV 5 and 8 E6 expression reduces ATM protein levels and attenuates LINE-1 retrotransposition. Virology 443:69-79
Ade, Catherine; Roy-Engel, Astrid M; Deininger, Prescott L (2013) Alu elements: an intrinsic source of human genome instability. Curr Opin Virol 3:639-45
Streva, Vincent A; Faber, Zachary J; Deininger, Prescott L (2013) LINE-1 and Alu retrotransposition exhibit clonal variation. Mob DNA 4:16

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