The adaptive immune system relies on the diversity of receptors expressed on the surface of B-and T cells to protect the organism from a vast amount of pathogenic threats. The proliferation and degradation dynamics of different cell types (B cells, T cells, naive, memory) is governed by a variety of antigenic and environmental signals, yet the observed clone sizes follow a universal power-law distribution. Guided by this reproducibility we propose effective models of somatic evolution where cell fate depends on an effective fitness. This fitness is determined by growth factors acting either on clones of cells with the same receptor responding to specific antigens, or directly on single cells with no regard for clones. We identify fluctuations in the fitness acting specifically on clones as the essential ingredient leading to the observed distributions. Combining our models with experiments, we characterize the scale of fluctuations in antigenic environments and we provide tools to identify the relevant growth signals in different tissues and organisms. Our results generalize to any evolving population in a fluctuating environment.immune repertoire | population dynamics | fluctuating fitness | lymphocyte receptor | repertoire sequencing A ntigen-specific receptors expressed on the membrane of B-and T cells (B-cell receptors, BCRs and T-cell receptors, TCRs) recognize pathogens and initiate an adaptive immune response (1). An efficient response relies on the large diversity of receptors that is maintained from a source of newly generated cells, each expressing a unique receptor. These progenitor cells later divide or die, and their offspring make up clones of cells that share a common receptor. The sizes of clones vary, as they depend on the particular history of cell divisions and deaths in the clone. The clone-size distribution thus bears signatures of the challenges faced by the adaptive system. Understanding the form of the clone-size distribution in healthy individuals is an important step in characterizing the antigenic recognition process and the functioning of the adaptive immune system. It also presents an important starting point for describing statistical deviations seen in individuals with compromised immune responses.High-throughput sequencing experiments in different cell types and species (2-9) have allowed for the quantification of clone sizes and their distributions (2, 9-11). Previous population dynamics approaches to repertoire evolution have taken great care in precisely modeling these processes for each compartment of the population, through the various mechanisms by which cells grow, die, communicate, and change phenotype (12-17). However, one of the most striking properties of repertoire statistics revealed by high-throughput sequencing is the observation of power laws in clone-size distributions ( Fig. 1 A and B), which holds true for various species (human, mice, zebrafish), cell type (B-and T cells), and subsets (naive and memory, CD4 and CD8), and seems to be insensitive to these conte...
The simultaneous expression of the hunchback gene in the numerous nuclei of the developing fly embryo gives us a unique opportunity to study how transcription is regulated in living organisms. A recently developed MS2-MCP technique for imaging nascent messenger RNA in living Drosophila embryos allows us to quantify the dynamics of the developmental transcription process. The initial measurement of the morphogens by the hunchback promoter takes place during very short cell cycles, not only giving each nucleus little time for a precise readout, but also resulting in short time traces of transcription. Additionally, the relationship between the measured signal and the promoter state depends on the molecular design of the reporting probe. We develop an analysis approach based on tailor made autocorrelation functions that overcomes the short trace problems and quantifies the dynamics of transcription initiation. Based on live imaging data, we identify signatures of bursty transcription initiation from the hunchback promoter. We show that the precision of the expression of the hunchback gene to measure its position along the anterior-posterior axis is low both at the boundary and in the anterior even at cycle 13, suggesting additional post-transcriptional averaging mechanisms to provide the precision observed in fixed embryos.
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