Tomkins, Janine; (1996) Molecular and evolutionary investigation of the phosphoglucomutase gene family. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes molecular and evolutionary investigations of the phosphoglucomutase (PGM) gene family. The PGM loci (PGM1, PGM2 an6 PGM3) widely expressed in man are thought to be the products of a diverged gene family. Following the cloning of PGM1 in 1992, the primary aim of this project was to investigate approaches for cloning the other members of the gene family. The strategies investigated include the use of anti-PGM1 antibodies, low stringency PCR, degenerate primer PCR and searching EST databases. A variety of resources were used, including the human cell line K562. This cell line is devoid of PGM1 activity and the deficiency was found to be associated with a marked reduction in PGM1 mRNA, thereby providing a useful resource. Two novel DNA sequences, hyhbfan6 human ESTI have been partially characterized. Hyhbf was identified by degenerate primer PCR of human cDNA. Although it is a member of the PGM gene family, no evidence could be obtained to confirm the sequence was human and it is suspected to be of bacterial origin. The human ESTI sequence, however, represents a widely expressed gene, which shows alternative transcripts and a related sequence. Evidence suggests it is a candidate for PGM2. Evolution of the PGM1 gene was investigated in mammals. Nucleotide analysis of the great apes showed the PGM1*1+ is ancestral since the ape homologues have the same characteristic amino acid substitutions as man. Extensive phylogenetic analysis of prokaryotic and eukaryotic sequences identified through conserved functional protein domains was undertaken. Eight distinct evolutionary pathways were identified, two of which, represented by Mycoplasma pirum PMM and Saccharomyces cerevisiae AGM are thought to reflect the divergent evolution of PGM2 and PGM3.

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