Patterns of mutation in the human genome

Hodgkinson, Alan James (2011) Patterns of mutation in the human genome. Doctoral thesis (DPhil), University of Sussex.

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The processes that underlie point mutations in the human genome are largely unknown.
However, the cumulative effect of these processes have a large impact on how mutation
rates vary across a number of different scales and contexts, and consequently guide our
understanding of human disease and evolution. Although variation in the mutation rate
has been characterized on many different levels, it is not fully understood the extent to
which the rate of mutation can vary outside of the general patterns already observed.
Beginning with the human genome project, many studies have produced large unbiased
sequence datasets within a number of human populations. To that end, we analysed a
number of sequence datasets in an attempt to better understand the patterns and causes
of variation in the rate of mutation that exists across the genome. Firstly, we find that
the mutation rates of single sites vary by more than is currently understood, and that this
variation is not associated with any specific process or feature on either a local or
genomic scale. Although we have been unable to uncover the source of such variation,
understanding the range of mutability at sites in the human genome is important since it
may point to functional regions, disease phenotypes and prompt further ideas on the
underlying mechanisms associated with such a result. Furthermore, we find evidence
that a mutational process that can generate the simultaneous production of two new
alleles within the same individual during a single, or tightly linked series of mutation
events increases the number of tri-allelic sites in the human genome. There are a
number of potential mechanisms that may drive this process, and the consequences of
such an event may be far reaching, as the generation of two new alleles at a single site
in functional regions may allow a more rapid exploration of evolutionary space.
Furthermore, this process appears to make a reasonable contribution to variation in the
human genome, thus providing a substrate for evolutionary change. Finally, we observe
significant variation in the mutation rate over all scales in cancer genomes. Part of this result can be explained by the actions of specific carcinogens, however it is striking that
patterns of mutation can be both consistent across different cancer types, but also very
different between individuals with the same type of cancer over different scales. This
result points to the idea that the patterns of mutation may vary widely between different
genomes under different conditions, and the identification of general patterns in a small
number of samples may not fully describe the extent to which mutation rates can vary.
Taken together, these conclusions suggest that the patterns and processes underlying
mutation are highly complex, and require further analysis if they are to be fully

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biology and Environmental Science
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Library Cataloguing
Date Deposited: 01 Sep 2011 07:57
Last Modified: 17 Aug 2015 14:27

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