Genotype versus phenotype: conflicting results in mapping a lung tumor susceptibility locus to the G7c recombination interval in the mouse MHC class III region

Abstract

Susceptibility to chemically induced lung tumorigenesis has previously been mapped to a genomic interval of 27 kb in the MHC class III region of the mouse using two H2 (a/b) intra- H2 recombinants, B10.A(1R) and B10.A(2R). Three genes are located within this interval, G7e (encoding a viral envelope protein), G7a/ Vars2 (encoding valyl-tRNA synthetase), and G7c (a gene with unknown function). A 70 kb contig, spanning the 27 kb region and extending 20 kb either side, was constructed from lambda phage libraries with genomic inserts derived from mouse strains B10.A(1R) and B10.A(2R). The region was analyzed for single-nucleotide polymorphisms, which would facilitate further fine mapping of the interval. Analysis of the expression levels of the candidate genes did not reveal any difference between B10.A(1R) and B10.A(2R). In addition, no differences were found at the sequence level in the 27 kb interval except for an A to T transition in intron 7 of G7c. A database comparison of the sequence surrounding this polymorphism did not identify any DNA-binding or enhancer consensus sequence. In conclusion, the previously observed phenotype could not be associated with or assigned to any of the candidate genes G7e, G7a/ Vars2, or G7c, nor could any of the other susceptibility loci, which have been reported to map to this region ( Cps1, Acp, Orch1, and Igis1).

Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics

“…Of particular interest is the animal version of the Het-C domain which is currently known from chordates and the rotifer Adineta vaga . Like bacterial polymorphic toxins, it occurs in a cell-surface protein, which in vertebrates is encoded by the MHC class III region [207,208]. Given this architecture it is conceivable that it is deployed as a defensive toxin against fungal or bacterial pathogens.…”

mRNA expression analysis of cell cycle genes in islets of pregnant mice

“…Fignl1 had already been linked to the cell cycle, but up to now with discrepant effects [29, 30]. The last gene called, G7e , also known as D17H6S56E-5 , was essentially uncharacterised, although located in a tumour susceptibility locus [31, 32]. Expression of Fignl1 and G7e was strongly correlated with essential cell cycle genes in public human and mouse microarray databases, analysed via Multi Experiment Matrix: MEM [33] (ESM Tables 4 and 5).…”

“…Remarkably, the rodent-specific G7e (ESM Fig. 7b), located in the major histocompatibility complex class III, is homologous to the envelope protein of murine leukaemia virus and maps in a lung tumour susceptibility locus [31, 32]. The intriguing possibility therefore is that a virally transduced gene stably integrated in the mouse genome is expressed in a regulated manner in order to support cell division, but also controls susceptibility to tumour development.…”

VARS2 V552V variant as prognostic marker in patients with early breast cancer

“…Moreover, many cancers and autoimmune diseases are known to be linked to allelic differences in effector proteins, such as Vars2 (G7a), G7b, G7c, and Hsp70 in MHC class III [17][18][19][20][21]. Interestingly, the human genome encoding the p52 subunit of the TFIIH transcription/DNA repair factor, which functions with both an RNA polymerase II general transcription factor and a NER factor, has been identified as the homologue of the mouse gene containing G7a [22].…”