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.
Our aim i s to complete the determination of the structure, and the complete sequence, of the immunoglobulin heavy chain (Igh) locus in two strains of mice; we will complete the assembly of Bacterial Artificial Chromosome (BAC) contigs from 129 and C57BL/6; we will identify every variable region (Vh) gene with their 5' and 3' regulatory elements. Comparison of the two mouse haplotypes and the recently sequenced human IGH locus will identify shared combining site structures that are likely to be important to the defense of both species. Comparison will also reveal conserved noncoding sequence elements; these are likely to be control elements used in the regulation of this complex locus, and we will investigate their possible roles in regulating the activation, expression, and replication of Igh.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023548-18
Application #
6621499
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Kirkham, Perry M
Project Start
1985-09-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
18
Fiscal Year
2003
Total Cost
$360,000
Indirect Cost

  Institution

Name
Torrey Pines Institute for Molecular Studies
Department
Type
DUNS #
605758754
City
San Diego
State
CA
Country
United States
Zip Code

  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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