The long term objective of the proposed studies is to define the relationship between diversity of structure in MHC genes and the function of those genes in the immune system. The significance of these studies stems from the fact that our understanding of the role of MHC genes in immune function is largely derived from analyses based on polymorphisms defined in inbred mice. Since these structurally relevant polymorphisms influence function of the MHC products, it is of great interest to define which polymorphisms are relevant to the diversification of alleles within inbreeding populations and which are representative of individuals from genetically isolated populations.
The specific aims are: 1) To characterize a unique MHC haplotype by comparison with two other previously described haplotypes defining features of haplotype variation that are relevant to MHC function and evolution. 2) To determine if haplotypes other than H-2b undergo copy events that lead to diversification of gene encoding antigen presenting products of the class I and class II regions of the H-2 complex. 3) To define the relative contributions of spontaneous point mutations and copy mediated mutations in the diversification and polymorphism of MHC genes. The analyses will be accomplished by the molecular genetic comparison of cloned genes among genetically defined mouse strains. Cosmid and phage genomic libraries of A.CA, B10.M, C57BL/6 and C57BL/10 lines will be analyzed to isolate homologous class I and class II sequences. Comparative studies will be based on restriction endonuclease mapping and DNA sequence analyses of genes derived from each library. Synthetic oligonucleotide probes will be used to identify specific DNA sequences that are shared by MHC genes within and among the H-2f and H-2b haplotypes. Direct DNA sequence analysis of homologous portions of MHC genes will provide estimates of spontaneous mutation and copy mediated mutation rates as well as provide data pertaining to the number of generations the various haplotypes that have been used to define MHC variation have diverged from each other.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022420-03
Application #
3133448
Study Section
Immunobiology Study Section (IMB)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Yun, T J; Melvold, R W; Pease, L R (1997) A complex major histocompatibility complex D locus variant generated by an unusual recombination mechanism in mice. Proc Natl Acad Sci U S A 94:1384-9
Vallejo, A N; Pease, L R (1996) The locus-specific enhancer activity of the class I major histocompatibility complex interferon-responsive element is associated with a gamma-interferon (IFN)-inducible factor distinct from STAT1alpha, p48, and IFN regulatory factor-1. J Biol Chem 271:29813-21
Vallejo, A N; Allen, K S; Pease, L R (1995) A common mutation in the hominoid class I A-locus IFN-responsive element results in the loss of enhancer activity. Int Immunol 7:853-9
Vallejo, A N; Pease, L R (1995) Structure of the MHC A and B locus promoters in hominoids. Insights on the evolution of the class I MHC multigene family. J Immunol 154:3912-21
Pullen, J K; Tallquist, M D; Melvold, R W et al. (1994) Recognition of a single amino acid change on the surface of a major transplantation antigen is in the context of self peptide. J Immunol 152:3445-52
Pease, L R; Horton, R M; Pullen, J K et al. (1993) Amino acid changes in the peptide binding site have structural consequences at the surface of class I glycoproteins. J Immunol 150:3375-81
Altintas, A; Cai, Z; Pease, L R et al. (1993) Differential expression of H-2K and H-2D in the central nervous system of mice infected with Theiler's virus. J Immunol 151:2803-12
Hunt, H D; Munitz, T I; Pease, L R (1992) Alloreactive cytotoxic T lymphocytes recognize epitopes determined by both the alpha helices and beta sheets of the class I peptide binding site. J Exp Med 175:821-9
Hildebrand, W H; Horton, R M; Pease, L R et al. (1992) Nucleotide sequence analysis of H-2Df and the spontaneous in vivo H-2Dfm2 mutation. Mol Immunol 29:61-9
Cai, Z; Pease, L R (1992) Structural and functional analysis of three D/L-like class I molecules from H-2v: indications of an ancestral family of D/L genes. J Exp Med 175:583-96

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