Within genome variation of germ-line and somatic mutation

Smith, Thomas C A (2017) Within genome variation of germ-line and somatic mutation. Doctoral thesis (PhD), University of Sussex.

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Abstract

Variation in the mutation rate along the human genome, if not properly understood and accounted
for, has the potential to confound evolutionary studies, produce spurious driver candidates in cancer
studies, and hinder the diagnostics aimed at understanding the etiologies of genetic diseases.

In this thesis I consider mutation rate variation in both the germ-line and somatic tissues, at varying
scales. In the germ-line, the major advance of this thesis over previous works is use of direct
methods to analyse the magnitude, scale and determinants of mutation rate variation. This has
enabled us to tease apart the evolutionary and mutational forces, whilst directly quantifying the
variation in the human mutation rate at different scales; at large scales the variation appears to be
quite modest, however at the single nucleotide scale there is potentially huge cryptic variation in the
mutation rate. I envisage that within the near future, the increase in de novo mutations coming from
pedigree studies will allow for even greater understanding.

I extend this work into somatic tissues, however due to the quality of data and heterogeneity of
samples and cell types, the primary findings lean towards highlighting areas of improvement for
next genereation sequencing (NGS) pipelines - I show ~4% of all single nucleotide variants from
cancers appear to be errors - and develop methods with which future studies could provide more
insight. With these methods and the ever increasing flow of somatic single nucleotide variants,
coupled with the continual improvements in NGS technology, it should soon be possible to provide
accurate answers to the questions posed of somatic mutation rate variation in this thesis.

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: 24 May 2017 09:57
Last Modified: 24 May 2017 09:57
URI: http://sro.sussex.ac.uk/id/eprint/68212

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