GENOMIC PLASTICITY IN THE HUMAN U2 SNRNA GENE CLUSTER

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DESCRIPTION: (Adapted from the application.) The genes encoding U2 small nuclear RNA (snRNA) exist as a perfect tandem array of 5 to >22 copies of a 5.8 KB repeat unit on human chromosome 17q21. This locus is a fragile site which may be induced by adenovirus 12 infection. Further, the locus has been maintained at its present site for >35 Myr through multiple speciation events in the primate lineage. The Principal Investigator proposes a multi-faceted approach to understanding adenovirus-induced chromosome fragility. Six specific aims include: (1) U2 chromosomal sequences required for fragile site induction will be identified and analyzed; (2) The chromosomal functions required for adeno 12 virus fragility will be identified, including requirements for snRNA transcription, chromatin structure, methylation, topoisomerase binding, and the origin and scheduling of replication; (3) The requirement for a high concentration of transcription units for the existence of a fragile site will be determined; (4) The evolutionary history of this primate locus will be traced. DNA sequencing from a variety of primates, as well as human groups, will be performed to compare and investigate mechanisms of inheritance and linkage; (5) The influence of U2 repeat sequences on the rate, boundaries, and stability of gene amplification will be investigated; and (6) The domains and functions of the adenovirus 12 E1B 55 kDa protein which are required for inducing chromosome fragility will be characterized.