| Summary: | The aim of this work was to quantify the extent to which both mutation and natural selection have influenced molecular evolution in murid noncoding sequence. In particular, I investigated the magnitude of and variation in selective constraint, within murid noncoding DNA. Selective constraint is defined as the proportion of all mutations occurring at a locus or site which are strongly deleterious and therefore removed by selection. The approach adopted to estimate selective constraint relies on the assumption that we can quantify the past strength of purifying selection in a DNA sequence by comparison with nearby regions which are assumed to be evolving neutrally. To this end, work in this thesis deals with mutational variation and bias (Chapters 2 and 3) as well as with selective constraint (Chapters 4 and 5) in noncoding DNA. Chapter 2 is concerned with the differential effects of context-dependent mutation (namely, CpG hypermutability) at fourfold synonymous and noncoding sites. Chapter 3 is concerned with mutational variation in the murid genome. Nucleotide substitution rates in murid transposable elements were estimated. Our results indicate that greater mutational variation occurs along the length of a chromosome than between individual chromosomes. In Chapter 4, the level of constraint in intergenic DNA adjacent to coding sequences and a moderate distance inside first introns was estimated in a sample of 300 mouse-rat gene orthologues. The results suggested that whilst selective constraint in intergenic sequence adjacent to the start and stop codons is moderately high, this becomes statistically indistinguishable from zero within 4kb upstream/downstream of the first/last exon. Chapter 5 expands on the work done in Chapter 4. The results showed that, when repetitive sequence is removed, the selective constraints in intergenic DNA are significantly different from zero.
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