International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 114 - TRANSGENIC BAC RESCUE IN MICE IDENTIFIES THE HOST RESISTANCE GENE TO CYTOMEGALOVIRUS INFECTION, Cmv1

Mr. Seung-Hwan Lee
University of Ottawa
451 Smyth Road-Rm 4207
Ottawa,
Ontario K1H 8M5
Canada

Co-Authors: 2)Repentigny Y, 3) Kothary R, 4) Belouchi A, 5)Gros P 1) Vidal SM
Institutions: 2)Centre for Molecular Medicine, Ottawa Hospital Research Institute, 4)Calileo Genomics Inc., Department of Biochemistry, McGill University, 1)Department of Biochemistry, Microbiology and Immunology, University of Ottawa,

In mice, natural resistance to infection with cytomegalovirus is controlled by a chromosome 6 locus, Cmv1. To isolate Cmv1, we have used a positional cloning approach for which we assembled a 1.6 Mb BAC contig and established a transcript map of 20 transcription units within the critical interval. This region of the mouse chromosome is highly complex presenting different gene number in mouse strains. In addition, haplotype analysis in 18 inbred strains indicated two independent haplotypes for the susceptibility allele, Cmv1s, suggesting the presence of either interallelic heterogeneity or genetic heterogeneity. Finally, two strong genomic candidate regions were identified in the Cmv1 interval; candidate region 1, where Klra8 is located, is associated with cytomegalovirus susceptibility in the recombinant inbred strain BXD-8. KLRA8 is an activating NK cell receptor of the C-type lectin superfamily. Candidate region 2, where Est33 resides, represents the Cmv1 common region on two independent mapping efforts. Est33 is a novel highly polymorphic spleen-specific EST. The candidacy of these regions was evaluated in vivo by functional complementation using BAC transgenesis. Phenotypic analysis of the transgenic progeny together with STS content of the BAC constructs traced the resistance gene to a single region that is expressed independently of the genetic background, unequivocally demonstrating allelism between Cmv1 and Klra8.


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