Abstract

A long standing goal of immunogenetics has been to understand the genetic basis of antibody diversity and responsiveness, to understand both the mechanisms through which the apparently limitless variety of antibody sequences are created and the reasons these mechanisms are used. This knowledge may enable the manipulation of the antibody response - positively, to enhance vaccine response and efficacy, negatively, to dampen and suppress autoantibody or anti-organ graft responses. Among other possibilities a thorough understanding of the structural range of combining sites encoded in the genetic repertoire should lead to a rational and accelerated strategy for vaccine development. This project will completely define and catalogue the mouse immunoglobulin heavy chain (Igh) locus in two strains. This will be done by isolating the entire locus as overlapping clones in Yeast and Bacterial Artificial Chromosomes (YACs and BACs) from two mouse strains. All mouse Vh genes will be cloned and sequenced to create a complete directory of the mouse germline repertoire for two quite different haplotypes. These will be compared among themselves and with the human Vh gene directory to identify Vh genes that have important protective or other functions, to identify noncoding regulatory structures and to characterize the forces shaping the evolution of antibody genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023548-13
Application #
2671863
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1985-09-01
Project End
1998-10-31
Budget Start
1998-04-01
Budget End
1998-10-31
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Medical Biology Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Degner, Stephanie C; Verma-Gaur, Jiyoti; Wong, Timothy P et al. (2011) CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells. Proc Natl Acad Sci U S A 108:9566-71
Jhunjhunwala, Suchit; van Zelm, Menno C; Peak, Mandy M et al. (2008) The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions. Cell 133:265-79
Retter, Ida; Chevillard, Christophe; Scharfe, Maren et al. (2007) Sequence and characterization of the Ig heavy chain constant and partial variable region of the mouse strain 129S1. J Immunol 179:2419-27
Pawlitzky, Inka; Angeles, Christina V; Siegel, Andrea M et al. (2006) Identification of a candidate regulatory element within the 5' flanking region of the mouse Igh locus defined by pro-B cell-specific hypersensitivity associated with binding of PU.1, Pax5, and E2A. J Immunol 176:6839-51
Norio, Paolo; Kosiyatrakul, Settapong; Yang, Qiaoxin et al. (2005) Progressive activation of DNA replication initiation in large domains of the immunoglobulin heavy chain locus during B cell development. Mol Cell 20:575-87
Yang, Qiaoxin; Riblet, Roy; Schildkraut, Carl L (2005) Sites that direct nuclear compartmentalization are near the 5' end of the mouse immunoglobulin heavy-chain locus. Mol Cell Biol 25:6021-30
Jones Tiffany, Linda; Riblet, Roy; Stein, Kathryn E (2003) The Sr1 gene that controls diversity of the anti-inulin antibody response maps to mouse chromosome 14. Immunogenetics 55:80-6
Chevillard, Christophe; Ozaki, Jennifer; Herring, Christopher D et al. (2002) A three-megabase yeast artificial chromosome contig spanning the C57BL mouse Igh locus. J Immunol 168:5659-66
Zhou, Jie; Ermakova, Olga V; Riblet, Roy et al. (2002) Replication and subnuclear location dynamics of the immunoglobulin heavy-chain locus in B-lineage cells. Mol Cell Biol 22:4876-89
Zhou, Jie; Ashouian, Nasrin; Delepine, Marc et al. (2002) The origin of a developmentally regulated Igh replicon is located near the border of regulatory domains for Igh replication and expression. Proc Natl Acad Sci U S A 99:13693-8

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