Phased epigenetic fragility and stability accelerate the genetic evolution of B-cells
Non-genetic heterogeneity can provide population robustness when responding to threats or making developmental decisions, but when the biological process rests on specific individuals (tissue-resident macrophages or genetic evolution), non-genetic heterogeneity degrades performance. Vaccine responses depend on the Darwinian evolution of B-cells to generate high-affinity, genetically-encoded antibodies, yet B-cell decision-making is non-genetically variable. In fact, B-cell epigenetic states are fragile during selection but stable during the proliferation burst. Here we report that the iterative dynamics of epigenetic fragility and stability of B-cell fate decisions do not impair but accelerate affinity maturation, by modulating the generation and removal of high-affinity outliers on a fitness landscape that is non-monotonic defined not only by survival/proliferation but plasma cell differentiation. These insights reconcile classical B-cell clonal selection theory with experimentally observed dynamics of epigenetic variability. The resulting model correctly predicts emergent vaccine response properties in alternate mouse strains and may contribute to personalized vaccination strategies. HIGHLIGHTSO_LIB-cell epigenetic states are fragile during antigen selection but stable within proliferative bursts C_LIO_LIEpigenetic state fragility allows high affinity cells to escape plasma cell differentiation C_LIO_LIEpigenetic state stability within proliferative bursts maximizes progeny of fittest cells C_LIO_LIPhased epigenetic dynamics of B-cells predicts emergent vaccine response properties C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/661408v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1c2af9forg.highwire.dtl.DTLVardef@980003org.highwire.dtl.DTLVardef@128d8c0org.highwire.dtl.DTLVardef@ae48b8_HPS_FORMAT_FIGEXP M_FIG C_FIG