Origin and maintenance of germ‐line V genes

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Abstract
Summary: The distribution of nucleotide variability within and upstream of germ‐line VH186.2‐related variable genes was studied. The data in this report of work in progress indicate non‐random selection for variability in the second antigen‐contact or complementarity‐determining region (CDR2) for 12 such genes isolated using the polymerase chain reaction (PCR) technique from genomic C57BL/6 mouse liver DNA. The translated protein sequences of these and three additional previously published genes also display a pronounced Wu‐Kabat peak of amino acid variability in CDR2. In the CDR1 and CDR2 regions of this set of related germ‐line genes, there are no silent nucleotide changes, and most amino acid replacements (or non‐synonymous changes) are non‐conservative. In contrast, there is selection against amino acid replacements in the framework regions (FW), as indicated by the significant number of silent (or synonymous) mutational changes from the VH 186.2 reference sequence. This is surprisingly similar to the Wu‐Kabat variability patterns observed in somatically mutated immune response antibodies. These data could imply similar diversification mechanisms acting on B cell‐expressed V genes in the soma (i.e. in a germinal centre) and in the germ‐line DNA of male and/or female germ cells. While always possible, we consider this unlikely. Similarly, we consider as unlikely an explanation based on a classical Darwinian model involving simple stepwise whole animal selection prior to reproduction for each VH and VL gene now phylogenetically stored in the V segment arrays of the genomic DNA. A more reasonable hypothesis for the origin and maintenance of the many germ‐line V genes would propose that there is a yet to be defined process providing a direct genetic link between somatically mutated and selected V genes and the germ‐line DNA repertoire.