Antibody repertoires generated by VH replacement and direct VH to JH joining.
The immunoglobulin heavy chain repertoire is generated by somatic rearrangement of variable (V(H)), diversity (D(H)), and joining (J(H)) elements. It can be further diversified by V(H) replacement, where nonrearranged V(H) genes invade preexisting V(H)D(H)J(H) joints. To study the impact and mechanism of V(H) replacement, we generated mice in which antibody production depends on the replacement of a nonproductive V(H)D(H)J(H) rearrangement inserted into its physiological position in the immunoglobulin heavy chain locus. In these mice a highly diverse heavy chain repertoire resulted from V(H) replacement and a second process of noncanonical V(D)J recombination, direct V(H) to J(H) joining. V(H) replacement rarely generated detectable sequence duplications but often proceeded through recombination between the conserved homologous sequences at the 3' end of V(H). Thus, V(H) replacement is an efficient mechanism of antibody diversification, and its impact on the overall antibody repertoire could be greater than anticipated because it frequently leaves no molecular footprint.
Koralov
Sergei B
SB
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Novobrantseva
Tatiana I
TI
Königsmann
Jessica
J
Ehlich
Andreas
A
Rajewsky
Klaus
K
D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D049109:Cell Proliferation; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D006720:Homozygote; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007144:Immunoglobulin J-Chains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid
D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007135:Immunoglobulin Variable Region; D001120:Arginine