The long-term objectives of this proposal are an understanding of the functions and significance of interspersed repeated DNA families in the human genome. This includes cellular functions, mode of amplification and the effects that amplification have in altering the genome. A large portion of this project will involve a detailed characterization of the transcription and transposition of the Alu family of repetitive DNA sequences. The transcription studies will center on the in vivo use of the Alu family RNA polymerase III promoter and will also use human Alu family members introduced into mouse cells and also by an evolutionary study of a single, highly conserved genetic locus across phylogeny. These experiments are important in assessing the impact that 500,000 Alu family members in each cell with RMA polymerase III promoters will have on cellular transcription as well as the potential genome alterations caused by their transposition and amplification. A second family of sequences represent several hundred copies of a sequence which is homologous to the nuclear antigen coding region of Epstein-Barr virus (EBV). DNA sequences analysis, in vivo transcription studies and DNA polymorphism studies will be carried out on the human sequences. The goals will be to determine the relation between the human and EBV sequences and whether the human genome produces a related protein. Also, these experiments will determine whether these sequences are hot-spots for mutation and recombination since genetic translocations are associated with the transforming potential of the virus. There is a very low copy number sequence in the human genome that hybridizes to a small portion of the genome of bovine leukemia virus. The human sequences will be cloned and sequenced to determine the significance of the homology. Further mapping, transcription and gene enhancer studies will be carried out to determine the functions of both the human and viral sequences.
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