Starting from distinct foundation populations (F0) of outbred mice, five selections were carried out by bidirectional assortative breeding for high (H) or low (L) antibody responsiveness to natural immunogens (erythrocytes, Salmonella, and proteins). In each selection, the assortative mating of the highest responder mice generated the H line, and that of the lowest responder mice generated the L line. High or low antibody responsiveness resulted from the interaction of alleles at several independent loci, which accumulated progressively in H and L mice during the consecutive generations of selective breeding until homozygosity of the relevant loci was reached at the selection limit when the interline difference was maximal. Yet several immune parameters and associated traits were differently affected in the five selections, indicating that nonequivalent sets of genes were involved. To amplify the interline difference in antibody titer, a new selection (GS) was performed. Homologous H or L mice of the five selections were intercrossed to produce the F0H or F0L foundation population with a balanced frequency of the gene pools of the five homologous lines. Starting from F0H and F0L, H and L mice were selected for the weighed antibody responses to multiple immunizations with the same antigens used in the five original selections. After 16 generations, the interline difference in antibody titer to the selection antigens, as well as to other unrelated antigens, was much larger in the GS selection than in the previous five selections, suggesting that more genes with upward effects had accumulated in H mice or, rather, more genes with downward effects had accumulated in L mice during the GS selection, H and L mice at the 16th generation of this selection were inspected daily until spontaneous death and then autopsied for macroscopic and microscopic examination to investigate the effects of the selected genes on life span and tumor incidence. The cumulative mortality rate was found to be remarkably higher in L than in H mice, the difference being accounted for mostly by malignant lymphomas that were the major cause of death in L mice. The interline difference in life span and lymphoma incidence was much larger than that observed in previous selections. Thus, accumulation of genes with negative effects on immune responsiveness entails a profound life span shortening and a great increase in lymphoma incidence. Furthermore, the finding of a clear maternal effect for life span and lymphoma incidence suggests the possible involvement of environmental factors that influence these phenotypes during the selection of genes that affect antibody responsiveness.

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