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Title: The involvement of non-B DNA forming sequences in mediating missense mutations, micro-deletions and micro-insertions in human inherited disease
Author: Kamat, M. A.
ISNI:       0000 0004 5358 8549
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2014
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The involvement of the local DNA sequence features (repetitive elements capable of adopting non-B structures, hotspot motifs, mononucleotide runs and tandem repeats) and epigenetic marks in mediating germline missense and nonsense mutations, micro-deletions and micro-insertions causing human inherited disease and obtained from Human Gene Mutation Database (HGMD; was studied in silico. A novel algorithm with a linear running time has been designed to detect the non-B DNA forming repeats in DNA sequences. The distributions of these repeats in the vicinity of mutations were analysed. We found that ~15% of missense mutations, ~12% of nonsense mutations, ~28% of micro-deletions and ~21% of micro-insertions occurred within direct repeats and is explicable by the formation/resolution/correction of non-B slipped structures. Several novel mutational mechanisms such as slipped strand mispairing/non-B slipped structure formation/DNA repair, non-B triplex formation/DNA repair and hairpin loop formation/DNA repair mechanisms have been proposed to explain single basepair substitutions leading to the formation of respectively exact direct, mirror and inverted repeats from inexact repeats. The role of CpG dinucleotides, CpHpG trinucleotides in mediating single base-pair substitutions and 83 known hotspot motifs together with other repetitive elements was studied in the context of micro-deletions and micro-insertions. We found that the number of single basepair missense and nonsense mutations (C>T and G>A) in CpG or CpHpG oligonucleotides was significantly (Fisher’s Exact test; p<2.37×10-120 higher than would have occurred by chance. Three DNA hotspot motifs, Chinese hamster scaffold attachment region motif WWWAAHAWWA, DNA polymerase α frameshift hotspot motif TCCCCC and its mirror image motif, were found to be overrepresented in both ± 20bp and ±2bp vicinity of micro-deletions and micro-insertions. Enrichment in the post-translational histone modification marks and binding sites (H3k4me3, H3k36me3, CTCF binding sites, DHSs) was found in the vicinity of all types of mutations analysed whereas histone modification mark H3k27me3 was overrepresented in the vicinity of missense and micro-lesion mutations. Thus, this study is a first systematic ascertainment of the involvement of non-B DNA forming sequences and epigenetic marks in mediating subtle mutations causing or associated with human inherited disease. The results shed light on the plausible underlying mutational mechanisms that involve non-B DNA forming repeats.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available