Evidence for Shaping of Light Chain Repertoire by Structural Selection.

ABSTRACT

The naïve immunoglobulin (IG) repertoire in the blood differs from the direct output of the rearrangement process. These differences stem from selection that affects the germline gene usage and the junctional nucleotides. A major complication obscuring the details of the selection mechanism in the heavy chain is the failure to properly identify the D germline and determine the nucleotide addition and deletion in the junction region. The selection affecting junctional diversity can, however, be studied in the light chain that has no D gene. We use probabilistic and deterministic models to infer and disentangle generation and selection of the light chain, using large samples of light chains sequenced from healthy donors and transgenic mice. We have previously used similar models for the beta chain of T-cell receptors and the heavy chain of IGs. Selection is observed mainly in the CDR3. The CDR3 length and mass distributions are narrower after selection than before, indicating stabilizing selection for mid-range values. Within the CDR3, proline and cysteine undergo negative selection, while glycine undergoes positive selection. The results presented here suggest structural selection maintaining the size of the CDR3 within a limited range, and preventing turns in the CDR3 region.