The intergenic spacer of the mouse ribosomal genes contains repetitive 140-base-pair (bp) elements which we show are enhancers for RNA polymerase I transcription analogous to the 60/81-bp repetitive enhancers (enhancers containing a 60-bp and an 81-bp element) previously characterized from Xenopus laevis. In rodent cell transfection assays, the 140-bp repeats stimulated an adjacent mouse polymerase I promoter when located in cis and competed with it when located in trans. Remarkably, in frog oocyte injection assays, the 140-bp repeats enhanced a frog ribosomal gene promoter as strongly as did the homologous 60/81-bp repeats. Mouse 140-bp repeats also competed against frog promoters in trans. The 140-bp repeats bound UBF, a DNA-binding protein we have purified from mouse extracts that is the mouse homolog of polymerase I transcription factors previously isolated from frogs and humans. The DNA-binding properties of UBF are conserved from the mouse to the frog. The same regulatory elements (terminators, gene and spacer promoters, and enhancers) have now been identified in both a mammalian and an amphibian spacer, and they are found in the same relative order. Therefore, this arrangement of elements probably is consequences.widespread in nature and has important functionalThe genes coding for the large rRNAs of most eucaryotes are organized in a similar fashion. From yeast cells to humans, these genes are arranged in multiple tandem copies with precursor-coding regions separated from each other by intergenic spacers (reviewed in references 42 and 54). Recent work from a number of laboratories has suggested that, at least among the multicellular eucaryotes, there is also a broadly conserved arrangement of transcriptional regulatory elements in the spacer (reviewed in reference 49a). The ribosomal genes of the frog, Xenopus laevis, may be considered a paradigm for this type of organization since all of the known regulatory elements have been identified in this organism.A typical intergenic spacer from an X. laevis ribosomal gene is shown in the top line of Fig. 1, with the spacer from a mouse ribosomal gene shown below for comparison. In X. laevis, the intergenic spacer is bounded on the left by a site for 3'-end formation of the precursor (31) and on the right by the gene promoter that directs initiation of the precursor transcript. Between these points are located one or more spacer promoters (4, 41, 53) (the only other known promoters that are recognized by polymerase I), and downstream of the spacer promoters are repetitive 60-and 81-base-pair (bp) elements (60/81-bp elements) that act as enhancers for polymerase I transcription and are additive in effect (11,30,44,48). Between the enhancers and the gene promoter is a termination site (31, 40). The 60/81-bp enhancers bind a Xenopus transcription factor, xUBF, which also binds to the gene promoter (47) and is the frog homolog of human UBF (hUBF; 2) and rat UBF (rUBF; 48a), factors which also stimulate transcription from the gene promoters of these species. The frog...
The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Since variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.
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