title: Construction and phenotypic analysis of mice carrying a duplication of the major histocompatibility class I (MHC-I) locus.
abstract: Copy number variation (CNV) has been associated increasingly with altered susceptibility to human disease. Large CNVs are likely to incur disease risk or resilience via predictable changes in gene dosage that are relatively straightforward to model using chromosomal engineering in mice. The classical class I major histocompatibility locus (MHC-I) contains a dense set of genes essential for innate immune system function in vertebrates. MHC-I genes are highly polymorphic and genetic variation in the region is associated with altered susceptibility to a wide variety of common diseases. Here we investigated the role of gene dosage within MHC-I on susceptibility to disease by engineering a mouse line carrying a 1.9-Mb duplication of this region [called Dp(MHC-I)]. Extensive phenotypic analysis of heterozygous (3N) Dp(MHC-I) animals did not reveal altered blood and stem cell parameters, susceptibility to high-fat diet, death by cancer, or contact dermatitis. However, several measures of disease severity in a model of atherosclerosis were improved, suggesting dosage-sensitive modulators of cardiovascular disease. Homozygous Dp(MHC-I)/Dp(MHC-I) mice demonstrated embryonic lethality. These mice serve as a model for studying the consequences of targeted gene dosage alteration in MHC-I with functional and evolutionary implications.
authors: Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy. olga.ermakova@emma.cnr.it
authors: Olga
authors: O
authors: Ermakova
authors: Ekaterina
authors: E
authors: Salimova
authors: Lukasz
authors: L
authors: Piszczek
authors: Cornelius
authors: C
authors: Gross
mesh_terms: D000236:Adenoma / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics; D001786:Blood Glucose; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004431:Ear, External / Q000276:immunology / Q000473:pathology; D005260:Female; D020440:Gene Duplication; D005805:Genes, MHC Class I; D005818:Genetic Engineering; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000209:etiology / Q000235:genetics; D007414:Intestinal Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging; D014463:Ultrasonography
chemical_list: D001786:Blood Glucose; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D002784:Cholesterol