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Title: The regulation of splicing and the evolution of mammalian genes
Author: Parmley, Joanna Louise
ISNI:       0000 0001 3472 6043
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2007
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Mammalian genes are unusual in being especially rich in introns. Does the need to remove these non-coding sequences from the immature mRNA impact on the evolution of the flanking coding exons? Until relatively recently, one might a priori have supposed not, as the information within the immature mRNA that specified the location of intron-exon boundaries was considered to dominantly be within the introns. More recent evidence, however, has highlighted the role ofSR proteins, which bind to exonic splice enhancer' domains, in facilitating intronic splicing. Does the need for exons to specify such binding domains impact on their rate of evolution and, if so, what is the magnitude of such effects? In this thesis I show that, in mammals, synonymous mutations within exonic splice enhancers are under stronger purifying selection than those not in enhancers and that codon usage bias is, in part, determined by the need to specify such enhancers. Comparably, 'amino acid choice is biased and rates of non-synonymous evolution are lower when associated with splice enhancers. These results are non-trivial in magnitude. The effect of selection near intron-exon boundaries is approximately as important a predictor ofrates of protein evolution as are expression parameters. As regards the selection on synonymous mutations, by review of the literature I argue that it is no longer tenable to consider that synonymous mutations in mammals are neutrally evolving. The shift in our understanding stems from the provision ofsound mechanistic underpinnings regarding the targets of such selection (rather than reliance on indirect inferences). The possibility that selection on synonymous mutations might mislead methods to detect positive selection, when sliding window protocols are employed, is shown to be acute. These results have implications for diagnosing the mode ofsplicing with nothing more than a well-annotated genome and for inferring positive selection. They also suggest the possibility of intelligent adjustment of, transgenes so as to improve their efficacy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available