Todd, Roger Benedict; (2001) Molecular analysis of a 7q inversion associated with myelodysplasia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chromosome 7 abnormalities are observed in a wide range of myeloid disorders, particularly myelodysplasia (MDS) and acute myeloid leukaemia (AML). Monosomy 7 and 7q deletions are the most frequent abnormalities, although translocations and inversions involving 7q also occur. The region 7q22-q34 may include as many as four distinct minimal regions of deletion (MDRs) which are thought to contain one or more myeloid tumour suppressor genes. Previous work in this laboratory defined the proximal breakpoint of a constitutional 7q22-q34 inversion, carried in a cell line derived from a member of a family which has a history of MDS. A YAC clone spanning this breakpoint and PAC clones flanking this breakpoint were identified. This thesis describes the molecular cloning and sequencing of both breakpoints of this inversion and analysis of the breakpoint sequences. Contigs of PAC and cosmid clones spanning the proximal inversion breakpoint were constructed. FISH and Southern analyses employing these clones allowed the position of this breakpoint to be further refined. Both breakpoints were then cloned by PCR techniques and sequenced. Analysis of these sequences revealed that the proximal breakpoint was 40kb centromeric to the TAC2 (tachykinin 2) gene and that the distal breakpoint was 42kb telomeric to the SSBP (mitochondrial ssDNA-binding protein) gene. Regions of sequence homology to other genes and ESTs (expressed sequence tags) suggested the presence of additional expressed sequences close to both breakpoints which may have been disrupted by the inversion. Sequence alignments revealed small (3-4bp) duplications at both breakpoints, suggesting that the mechanism of the inversion involved the creation of staggered breaks and filling-in of the overhanging ends. A 190bp Alu-Alu deletion, partial consensus DNA topoisomerase II binding sites, chi-like sequences, partial V(D)J recognition signal sequences and a (CA)n repeat were also detected and may have contributed to the inversion.

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