Variability of the MUC1 gene: Possible functional significance

The MUC1 gene is a membrane associated mucin and is highly polymorphic at both the DNA, mRNA and protein level due to variation in the number of a tandemly repeated 60bp (20 amino-acid) motif (VNTR). This thesis extends the study of the polymorphism in the MUC1 gene to examine sequence differences in the individual tandem repeats as well as exploring disease associations in relation to MUC1 haplotypes. The studies revealed that MUC1 has a higher level of tandem repeat sequence variability than previously suspected, and this is a source of additional allelic diversity. In particular, MVR-PCR analysis was used to map the number and position of the nucleotide substitutions, which encode PESR instead of the usual PDTR in the immunodominant part of the MUC1 tandem repeats. Polymorphism of the MUC1 gene was studied in three different patient groups; namely women suffering from recurrent spontaneous miscarriage; patients with oesophageal carcinoma and patients with gastritis. For these studies the VNTR length variation was analysed (except in gastritis where the data were already available) as well as two polymorphisms flanking the tandem repeat array. Preliminary analysis of MVR maps was also completed. The results confirmed earlier observations that there is a high degree of linkage disequilibrium across the MUC1 gene. Allelic and haplotype frequencies differed in the groups of patients and controls and the possible implications of this in relation to disease susceptibility are discussed. VNTR and MVR analysis was performed on DNA from 5 chimpanzees to gain insight into the evolutionary history of the MUC1 tandem repeat array. The tandem repeat array was shown to be significantly shorter in the chimpanzees. The alternative repeat PESR was not detected but there was a further nucleotide change that had not been seen in humans