STRONG INTRINSIC BIASES TOWARDS MUTATION AND CONSERVATION OF BASES INHUMAN IGV(H) GENES DURING SOMATIC HYPERMUTATION PREVENT STATISTICAL-ANALYSIS OF ANTIGEN SELECTION

Immunoglobulin V region genes acquire point mutations during affinity maturation of the T-cell-dependent B-cell response. It has been propos ed that both selection by antigen and characteristics of the DNA seque nce are involved in determining the distribution of mutations along th e genes. There is a tendency for replacement mutations to occur in the complementarity-determining regions and for silent mutations to accum ulate in the framework regions of used genes. By analysing a group of highly mutated human IgV(H)4-34 (V(H)4.21) and family 5 genes derived from human gut-associated lymphoid tissues, which were out-of-frame be tween V-H and J(H) (and therefore not used) we have investigated the d istribution of mutations acquired in the absence of selection. We obse rved that these genes may show the statistical hallmarks of selected g enes, suggesting that intrinsic biases alone may be enough to give the appearance of selection. These data suggest that analysis of the dist ribution of mutations in IgV(H) genes cannot be used reliably to state whether antigenic selection of the B-cell carrying the genes occurred . In-frame genes had more silent mutations than the out-of-frame genes and lacked stop codons. These characteristics were considered to be i ndicative of selection in the in-frame genes derived from human gut-as sociated lymphoid tissue.