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Title: DNA sequence context of micro-deletions and micro-insertions causing human genetic disease
Author: Ball, Edward Vincent
ISNI:       0000 0004 2747 4337
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2005
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I was responsible for developing the Human Gene Mutation Database (HGMD), which represents a comprehensive core collection of data on germ-line mutations in nuclear genes underlying or associated with human inherited disease ( This was essential to provide a high quality resource for the meta-analysis of human mutation data. HGMD currently contains 8181 (17%) micro- deletions (<20 bp) and 3268 (7%) micro-insertions (< 20 bp) in 918 and 652 genes respectively. A positive correlation was found between the frequencies of micro- deletions and micro-insertions for the 564 genes for which both micro-deletions and micro-insertions were reported suggesting that the likelihood of a micro-deletion and a micro-insertion co-occurring in a given gene are related. When the micro-deletion study was initiated, the data-set contained 3767 micro-deletions from 426 genes, whilst the micro-insertion study utilized a data-set of 1960 micro-insertions from 307 genes. Micro-deletions and micro-insertions of 1 bp constituted 48% and 66% of the respective totals and a negative correlation was found with the number of base-pairs deleted or inserted. However, the frequencies of micro-deletions and micro-insertions of 3 bp and 6 bp were significantly lower than predicted, suggesting that a proportion of these do not come to clinical attention. Many of the micro-deletions and micro- insertions were explicable by slipped mispairing, particularly micro-insertions, with 89% being explicable by DNA sequence duplication. Several sequence motifs were found to be over-represented in the vicinity of both micro-deletions and micro-insertions, including the CCCCCTG motif which shares homology with part of the prokaryotic Chi recombination hotspot (GCWGGWGG). A previously reported indel hotspot motif GTAAGT and its complement ACTTAC were found to be over-represented in the vicinity of both micro-deletions and micro-insertions, representing the first example of a mutational hotspot common to different types of lesion. Other motifs that were over-represented in the vicinity of both types of lesion included DNA polymerase pause sites and topoisomerase cleavage sites. Thus, micro-deletions and micro-insertions exhibit strong similarities in terms of the characteristics of their flanking DNA sequences, implying that they are generated by very similar underlying mechanisms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available