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The impact of endogenous retrovirus-like sequences on the human genome Goodchild, Nancy L.


Transposable elements comprise ~10% of the human genome and are hypothesized to play a significant role in genome variability and gene regulation. My work has focused on the RTVL-H family of human endogenous retroviruses and the possible impact these elements may have had and continue to have on the human genome. The evolutionary history of the RTVL-H family within the primate lineage was examined using several approaches. My findings suggest that the RTVL-H family has undergone two successive waves of amplification during primate evolution. The major amplification of RTVL-H elements appears to have occurred very early within the Old World primate lineage, after its divergence from the New World monkeys. The genomes of humans, apes and Old World monkeys are estimated to contain 50-100 copies of undeleted elements and 800-1000 copies of deleted sequences. This is in contrast to the New World monkey, marmoset, genome which contains only a handful of intact elements and ~50 deleted sequences. A second expansion of deleted elements appears to have occurred within a common ancestor of the ape lineage and was associated with a novel long terminal repeat (LTR) subtype. The structure of RTVL-H elements and their distribution in the genome suggest that RTVL-H elements amplified via retrotransposition. I have found evidence for this through the identification of an RTVL-H element in the orangutan genome that appears to represent the reverse transcription and integration of a spliced RTVL-H transcript. An apparent spliced genomic element found in human DNA lacks an intact 5’ LTR and may represent a processed RTVL-H pseudogene. This element appears to be polymorphic in the human population. I have also laid the ground work for a strategy to demonstrate RTVL-H retrotransposition within an experimental time frame. This strategy uses a “retro- transposition indicator gene” and allows for the direct selection of a retrotransposition event. RTVL-H LTRs contain transcriptional regulatory sequences and thus may affect the expression of adjacent cellular sequences. I have identified a clone, termed cPj-LTR, containing an ORF of 223 aa that has been polyadenylated within an RTVL-H LTR. The corresponding gene, termed PLT, is a novel, multi-exon locus that appears to have been evolutionarily conserved. Northern analysis identified several PLT-related transcripts in placental RNA samples, one of which appears to be associated with the LTR. The presence of this PLT-LTR fusion transcript was confirmed by PCR. Analysis of additional PLT cDNA clones suggests that the PLT mRNA undergoes alternative splicing at its 3’ end, with polyadenylation within an RTVL-H LTR occurring in one of the resulting transcripts.

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