Chapter 17, Problem 27
During an examination of the genomic sequences surrounding the human β-globin gene, you discover a region of DNA that bears sequence resemblance to the glucocorticoid response element (GRE) of the human metallothionein IIA (hMTIIA) gene. Describe experiments that you would design to test (1) whether this sequence was necessary for accurate β-globin gene expression and (2) whether this sequence acted in the same way as the hMTIIA gene's GRE.
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Regulation of the lac operon in E. coli (see Chapter 16) and regulation of the GAL system in yeast are analogous in that they both serve to adapt cells to growth on different carbon sources. However, the transcriptional changes are accomplished very differently. Consider the conceptual similarities and differences as you address the following.
Compare and contrast how these two systems are negatively regulated such that they are downregulated in the presence of glucose.
Incorrectly spliced RNAs often lead to human pathologies. Scientists have examined cancer cells for splice-specific changes and found that many of the changes disrupt tumor-suppressor gene function [Xu and Lee (2003). Nucl. Acids Res. 31:5635–5643]. In general, what would be the effects of splicing changes on these RNAs and the function of tumor-suppressor gene function? How might loss of splicing specificity be associated with cancer?
Mutations in the low-density lipoprotein receptor (LDLR) gene are a primary cause of familial hypercholesterolemia. One such mutation is a SNP in exon 12 of the LDLR. In premenopausal women, but not in men or postmenopausal women, this SNP leads to skipping of exon 12 and production of a truncated nonfunctional protein. It is hypothesized that this SNP compromises a splice enhancer [Zhu et al. (2007). Hum Mol Genet. 16:1765–1772]. What are some possible ways in which this SNP can lead to this defect, but only in premenopausal women?
RNA helicases are a class of proteins that bind mRNAs and influence their secondary structures and interactions with other proteins. RNA helicases have been implicated in many steps of RNA regulation such as splicing, decay, and translation. Why might these enzymes be so ubiquitously required for RNA regulation?
Marine stickleback fish have pelvic fins with long spines that provide protection from larger predatory fish. Some stickleback fish were trapped in lakes and have adapted to life in a different environment. Many lake populations of stickleback fish lack pelvic fins. Shapiro et al. (2004) (Nature 428:717.723) mapped the mutation associated with the loss of pelvic fins to the Pitx1 locus, a gene expressed in pelvic fins, the pituitary gland, and the jaw. However, the coding sequence of the Pitx1 gene is identical in marine and lake stickleback [Chan et al. (2010). Science 327:5963,302–305]. Moreover, when the Pitx1 coding region is deleted, the fish die with defects in the pituitary gland and the jaw, and they lack pelvic fins. Explain how a mutation near, but outside of, the coding region of Pitx1 may cause a loss of pelvic fins without pleiotropic effects on the pituitary gland and jaw.