Soma-to-germline feedback is implied by the extreme polymorphism at IGHV relative to MHC: The manifest polymorphism of the MHC appears greatly exceeded at Immunoglobulin loci, suggesting antigen-selected somatic V mutants penetrate Weismann's Barrier

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Abstract

Soma-to-germline feedback is forbidden under the neo-Darwinian paradigm. Nevertheless, there is a growing realization it occurs frequently in immunoglobulin (Ig) variable (V) region genes. This is a surprising development. It arises from a most unlikely source in light of the exposure of co-author EJS to the haplotype data of RL Dawkins and others on the polymorphism of the Major Histocompatibility Complex, which is generally assumed to be the most polymorphic region in the genome (spanning ˜4 Mb). The comparison between the magnitude of MHC polymorphism with estimates for the human heavy chain immunoglobulin V locus (spanning ˜1 Mb), suggests IGHV could be many orders of magnitude more polymorphic than the MHC. This conclusion needs airing in the literature as it implies generational churn and soma-to-germline gene feedback. Pedigree-based experimental strategies to resolve the IGHV issue are outlined.

Somatic mutations in CDR1 and CDR2 (red) or CDR 3 regions (green) of VDJ genes are clonally selected in B lymphocytes. RNA or cDNA copies penetrate Weismann's Barrier for targeted homologous integration (x, gene conversion) of the V portions (harboring CDR1, 2) into similar germline VH segments.

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