Figure 1.

Dynamic combination of deterministic and stochastic features enforces allelic exclusion at V-D-J containing gene loci. (a) Illustration of a V-DJ recombination factory as proposed by Lucas et al. (Curr Opin Cell Biol 2011;23:318–24). The diagram illustrates rosette-like structures at an antigen receptor allele that would bring remote V gene segments in proximity to a cis-linked, RAG-loaded DJ-recombined intermediate product. At homologous alleles, stochastic proceeding of V-to-DJ recombination is assumed to mostly contribute to the V-D-J assembly time of the given locus [illustrated by the dark brown sections in (b)]. (b) Schematic depiction of stochastic modelling of DNA rearrangement at V-D-J containing antigen receptor alleles based on the Markov process formalism, as described by Farcot et al. (J Immunol 2010;185:1622–32). The recombination window defines the time period along developmental maturation of a single lymphoid cell during which all requirements for sequential rearrangements (including epigenetics) could be met (hence during which recombination of the given locus could occur). The blue, brown and red sections represent the time course of mono-allelic behaviours in a collection of individual single cells from, respectively, (i) the transition from germline (GL) to DJ-rearranged (DJ) allelic statuses, (ii) the transition from DJ-rearranged to VDJ-rearranged (VDJ) allelic statuses, and (iii) the residence of productively rearranged (VDJ⁺) alleles [or of non-productively rearranged (VDJ⁻) alleles; depicted in light brown in the upper right diagram of part (c)] till the recombination window comes to an end. Transition times τ_DJ and τ_VDJ correspond to the time lapses required in the particular case to achieve steps (i) and (ii), respectively; τ_f corresponds to the time lapse required to achieve feedback inhibition (red bar). (c) Statistical compilation of biallelic behaviours and their contribution to the VDJ⁺/DJ, VDJ⁻/VDJ⁺, VDJ⁺/VDJ⁺ and VDJ⁺/GL final genomic distribution. The probabilistic curves (Prob) for the τ_DJ, τ_VDJ, and τ_f parameters are shown on the top, with the locations of the mean values indicated ().