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Title: Characterisation of a cluster of novel genes in the human major histocompatibility complex
Author: Olavesen, Mark G.
ISNI:       0000 0001 3456 2210
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1993
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The human MHC has been shown to be associated with susceptibility to a large number of diseases. Within the MHC class III region, which consists of a ~1,100kb segment of DNA located between the class I and class II multigene families, at least 38 genes have been identified, some of which could be involved in disease susceptibility. Analyses of the homologous mouse H-2S region have localised two loci responsible for susceptibility to experimental autoimmune orchitis, Orch-1, and corticosteroid-induced cleft palate, Cps-1, to an ~100kb segment of DNA. The characterisation of four genes located within the homologous region of the human MHC class III region is described here. The G7 gene is a novel gene located 58kb telomeric of the HSP70-Hom locus. G7 has been sequenced at the cDNA and genomic levels. The G7 gene, which contains 27 exons that span ~22kb of DNA, is expressed as an ~3kb mRNA. This mRNA was shown to be present at low levels in all of the cell types analysed, and was most abundant in monocytes and macrophages. Sequence analysis of cDNA clones revealed that the G7 mRNA contains two alternatively spliced exons which alter the putative G7 protein at the C-terminus. The different mRNA species encode putative protein products of 747 and 788 amino acids. The putative G7 proteins appear to be intracellular although their function remains to be determined. However, the putative G7 protein sequences do share significant similarity with bacterial DNA mismatch repair proteins and other similar proteins in yeast, mouse and man. A Pvull RFLP associated with the G7 gene was shown to result in a potential Thr → Ala amino acid substitution in ~25% of the haplotypes analysed. The G7b gene is another novel gene which is located between the HSP70-Hom and valyl-tRNA synthetase (VARS2) genes and may be homologous to other genes elsewhere in the human genome. G7b has been sequenced at the cDNA and genomic levels. The G7b gene contains 5 exons that span ~10kb. The G7b gene expressed an ~0.9kb mRNA that was present in all of the cell types analysed and was most abundant in monocytes and macrophages. The G7b cDNA clones encode a putative G7b protein of 95 amino acids. Polyclonal antisera have been raised against the putative G7b protein which detected an ~5kDa protein in U937 cell lysates. Therefore, the putative G7b protein appears to be an intracellular protein for which the function remains to be determined. However, the putative G7b protein shares significant sequence similarity to the human small ribonucleoprotein Sm-D for which autoantibodies are present in patients with SLE. A new gene G7c located between the G7 and valyl-tRNA synthetase (VARS2) genes has been identified as a result of the presence of non-repetitive sequence in the intergenic region that were shown to be conserved between species. Exon trapping analysis has identified two discrete exons from within this region. The mouse homologue of the human HSP70-Hom gene, Hsc70t, is a potential candidate gene for the Orch-1 locus. As a result it was been sequenced in H-2 congenic mouse strains known to be resistant and susceptible to experimental autoimmune orchitis. Sequence polymorphism was detected although this did not correlate with resistance or susceptibility to the disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry