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Gene Conversion-Like Events in the Diversification of Human Rearranged IGHV3-23*01 Gene Sequences
Bhargavi Duvvuri1, Gillian E Wu
1School of Kinesiology and Health Science, Faculty of Health, York University Toronto, ON, Canada.
Frontiers in Immunology
|June 21, 2012
Summary
Gene conversion (GCV)-like events in human immunoglobulin genes, mediated by activation-induced cytidine deaminase (AID), were identified. These events are more frequent in healthy individuals than CVID patients and absent in AID-deficient patients, suggesting a role in immune defense.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Gene conversion (GCV) is a known mechanism for immunoglobulin diversification in some species, but evidence in human immunoglobulin genes is limited.
- The presence of similar germline sequences and the necessary enzymes suggests GCV should occur in humans, making its scarcity puzzling.
- Investigating GCV-like activity in human immunoglobulin genes is crucial for understanding immune system diversity and function.
Purpose of the Study:
- To computationally analyze rearranged IGHV3-23(*)01 gene sequences to identify "GCV-like" activities.
- To investigate the role of activation-induced cytidine deaminase (AID) and structural features in GCV-like events.
- To compare the frequency of GCV-like events in healthy individuals, common variable immunodeficiency (CVID) patients, and AID-deficient patients.
Main Methods:
- Computational analysis of rearranged IGHV3-23(*)01 gene sequences from total PBMC RNA and single-cell PCR.
- Examination of sequences from healthy individuals, CVID patients, and AID-deficient patients.
- Structural modeling to analyze the DNA structure around GCV-like tracts and AID hotspot motifs.
Main Results:
- Strong evidence of GCV-like activity was identified in rearranged IGHV3-23(*)01 gene sequences.
- GCV-like tracts were observed to be flanked by AID hotspot motifs and located within single-stranded DNA (ssDNA) of stable stem-loop structures (SLSs).
- GCV-like events were significantly more frequent in healthy individuals than in CVID patients and were absent in AID-deficient patients.
Conclusions:
- GCV-like activity, potentially initiated by AID targeting ssDNA in stable SLSs, occurs in human immunoglobulin genes.
- The higher frequency in healthy individuals suggests a role in adaptive immunity, contrasting with CVID patients.
- GCV-like events, capable of extensive amino acid changes, may enhance antibody affinity and protect against rapidly evolving pathogens.
Keywords:
DNA secondary structureactivation-induced cytidine deaminaseaffinity maturationgene conversionhomologous recombinationhuman immunoglobulin geneMore Related Videos
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