The restricted DH gene reading frame usage in the expressed human antibody repertoire is selected based upon its amino acid content

The Ab repertoire is not uniform. Some variable, diversity, and joining genes are used more frequently than others. Nonuniform usage can result from the rearrangement process, or from selection. To study how the Ab repertoire is selected, we analyzed one part of diversity generation that cannot be d...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2013-06, Vol.190 (11), p.5567-5577
Main Authors: Benichou, Jennifer, Glanville, Jacob, Prak, Eline T Luning, Azran, Roy, Kuo, Tracy C, Pons, Jaume, Desmarais, Cindy, Tsaban, Lea, Louzoun, Yoram
Format: Article
Language:English
Subjects:
Adult
Amino Acid Sequence
Antibody Diversity - genetics
B-Lymphocyte Subsets - metabolism
Base Sequence
Codon, Terminator
Complementarity Determining Regions - chemistry
Complementarity Determining Regions - genetics
Female
Gene Expression
Gene Rearrangement
High-Throughput Nucleotide Sequencing
Humans
Immunoglobulin A - genetics
Immunoglobulin A - metabolism
Immunoglobulin G - genetics
Immunoglobulin G - metabolism
Immunoglobulin Heavy Chains - chemistry
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Joining Region - chemistry
Immunoglobulin Joining Region - genetics
Immunoglobulin M - genetics
Immunoglobulin M - metabolism
Immunoglobulin Variable Region - chemistry
Immunoglobulin Variable Region - genetics
Male
Middle Aged
Reading Frames
Reproducibility of Results
V(D)J Recombination
Young Adult
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The Ab repertoire is not uniform. Some variable, diversity, and joining genes are used more frequently than others. Nonuniform usage can result from the rearrangement process, or from selection. To study how the Ab repertoire is selected, we analyzed one part of diversity generation that cannot be driven by the rearrangement mechanism: the reading frame usage of DH genes. We have used two high-throughput sequencing methodologies, multiple subjects and advanced algorithms to measure the DH reading frame usage in the human Ab repertoire. In most DH genes, a single reading frame is used predominantly, and inverted reading frames are practically never observed. The choice of a single DH reading frame is not limited to a single position of the DH gene. Rather, each DH gene participates in rearrangements of differing CDR3 lengths, restricted to multiples of three. In nonproductive rearrangements, there is practically no reading frame bias, but there is still a striking absence of inversions. Biases in DH reading frame usage are more pronounced, but also exhibit greater interindividual variation, in IgG(+) and IgA(+) than in IgM(+) B cells. These results suggest that there are two developmental checkpoints of DH reading frame selection. The first occurs during VDJ recombination, when inverted DH genes are usually avoided. The second checkpoint occurs after rearrangement, once the BCR is expressed. The second checkpoint implies that DH reading frames are subjected to differential selection. Following these checkpoints, clonal selection induces a host-specific DH reading frame usage bias.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1201929