arXiv subjects

Thierry Mora

Publications and source records attributed to Thierry Mora.

At least 73 records · Page 4Linked to original sources

arXiv2018

OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

Motivation: High-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. Since the function of a receptor really depends on its protein sequence, it is important to be able to predict this probability of generation at the amino acid level. However, brute-force summation over all the nucleotide sequences with the correct amino acid translation is computationally intractable. The purpose of this paper is to present a solution to this problem. Results: We use dynamic programming to construct an efficient and flexible algorithm, called OLGA (Optimized Likelihood estimate of immunoGlobulin Amino-acid sequences), for calculating the probability of generating a given CDR3 amino acid sequence or motif, with or without V/J restriction, as a result of V(D)J recombination in B or T cells. We apply it to databases of epitope-specific T-cell receptors to evaluate the probability that a typical human subject will possess T cells responsive to specific disease-associated epitopes. The model prediction shows an excellent agreement with published data. We suggest that OLGA may be a useful tool to guide vaccine design. Availability: Source code is available at https://github.com/zsethna/OLGA

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arXiv2018

Cost and benefits of CRISPR spacer acquisition

CRISPR-Cas mediated immunity in bacteria allows bacterial populations to protect themselves against pathogens. However, it also exposes them to the dangers of auto-immunity by developing protection that targets its own genome. Using a simple model of the coupled dynamics of phage and bacterial populations, we explore how acquisition rates affect the survival rate of the bacterial colony. We find that the optimal strategy depends on the initial population sizes of both viruses and bacteria. Additionally, certain combinations of acquisition and dynamical rates and initial population sizes guarantee protection, due to a dynamical balance between the evolving population sizes, without relying on acquisition of viral spacers. Outside this regime, the high cost of auto-immunity limits the acquisition rate. We discuss these optimal survival strategies in terms of recent experiments.

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arXiv2018

Receptor crosstalk improves concentration sensing of multiple ligands

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems leading to crosstalk between different receptors. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of non-cognate ligands can interfere with the detection of the receptor's cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the non-cognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.

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arXiv2018

Detecting T-cell receptors involved in immune responses from single repertoire snapshots

Hypervariable T-cell receptors (TCR) play a key role in adaptive immunity, recognising a vast diversity of pathogen-derived antigens. High throughput sequencing of TCR repertoires (RepSeq) produces huge datasets of T-cell receptor sequences from blood and tissue samples. However, our ability to extract clinically relevant information from RepSeq data is limited, mainly because little is known about TCR-disease associations. Here we present a statistical approach called ALICE (Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences) that identifies TCR sequences that are actively involved in the current immune response from a single RepSeq sample, and apply it to repertoires of patients with a variety of disorders - autoimmune disease (ankylosing spondylitis), patients under cancer immunotherapy, or subject to an acute infection (live yellow fever vaccine). The method's robustness is demonstrated by the agreement of its predictions with independent assays, and is supported by its ability to selectively detect responding TCR in the memory but not in the naive subset. ALICE requires no longitudinal data collection nor large cohorts, and is thus directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with a wide variety of diseases and conditions, which can be used for diagnostics, rational vaccine design and evaluation of the adaptive immune system state.

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arXiv2018

Modeling the correlated activity of neural populations: A review

The principles of neural encoding and computations are inherently collective and usually involve large populations of interacting neurons with highly correlated activities. While theories of neural function have long recognized the importance of collective effects in populations of neurons, only in the past two decades has it become possible to record from many cells simulatenously using advanced experimental techniques with single-spike resolution, and to relate these correlations to function and behaviour. This review focuses on the modeling and inference approaches that have been recently developed to describe the correlated spiking activity of populations of neurons. We cover a variety of models describing correlations between pairs of neurons as well as between larger groups, synchronous or delayed in time, with or without the explicit influence of the stimulus, and including or not latent variables. We discuss the advantages and drawbacks or each method, as well as the computational challenges related to their application to recordings of ever larger populations.

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arXiv2018

Precise tracking of vaccine-responding T-cell clones reveals convergent and personalized response in identical twins

T-cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framework to data from three pairs of identical twins immunized with the yellow fever vaccine. We identified 500-1500 responding TCRs in each donor and validated them using three independent assays. While the responding TCRs were mostly private, albeit with higher overlap between twins, they could be well predicted using a classifier based on sequence similarity. Our method can also be applied to samples obtained post-infection, making it suitable for systematic discovery of new infection-specific TCRs in the clinic.

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arXiv2018

Predicting the spectrum of TCR repertoire sharing with a data-driven model of recombination

Despite the extreme diversity of T cell repertoires, many identical T-cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely-shared sequences, often referred to as `public', have been suggested to be over-represented due to their potential immune functionality or their ease of generation by V(D)J recombination. Here we show that even for large cohorts the observed degree of sharing of TCR sequences between individuals is well predicted by a model accounting for by the known quantitative statistical biases in the generation process, together with a simple model of thymic selection. Whether a sequence is shared by many individuals is predicted to depend on the number of queried individuals and the sampling depth, as well as on the sequence itself, in agreement with the data. We introduce the degree of publicness conditional on the queried cohort size and the size of the sampled repertoires. Based on these observations we propose a public/private sequence classifier, `PUBLIC' (Public Universal Binary Likelihood Inference Classifier), based on the generation probability, which performs very well even for small cohort sizes.

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arXiv2018

Separating intrinsic interactions from extrinsic correlations in a network of sensory neurons

Correlations in sensory neural networks have both extrinsic and intrinsic origins. Extrinsic or stimulus correlations arise from shared inputs to the network, and thus depend strongly on the stimulus ensemble. Intrinsic or noise correlations reflect biophysical mechanisms of interactions between neurons, which are expected to be robust to changes of the stimulus ensemble. Despite the importance of this distinction for understanding how sensory networks encode information collectively, no method exists to reliably separate intrinsic interactions from extrinsic correlations in neural activity data, limiting our ability to build predictive models of the network response. In this paper we introduce a general strategy to infer {population models of interacting neurons that collectively encode stimulus information}. The key to disentangling intrinsic from extrinsic correlations is to infer the {couplings between neurons} separately from the encoding model, and to combine the two using corrections calculated in a mean-field approximation. We demonstrate the effectiveness of this approach on retinal recordings. The same coupling network is inferred from responses to radically different stimulus ensembles, showing that these couplings indeed reflect stimulus-independent interactions between neurons. The inferred model predicts accurately the collective response of retinal ganglion cell populations as a function of the stimulus.

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arXiv2018

A simple model for low variability in neural spike trains

Neural noise sets a limit to information transmission in sensory systems. In several areas, the spiking response (to a repeated stimulus) has shown a higher degree of regularity than predicted by a Poisson process. However, a simple model to explain this low variability is still lacking. Here we introduce a new model, with a correction to Poisson statistics, which can accurately predict the regularity of neural spike trains in response to a repeated stimulus. The model has only two parameters, but can reproduce the observed variability in retinal recordings in various conditions. We show analytically why this approximation can work. In a model of the spike emitting process where a refractory period is assumed, we derive that our simple correction can well approximate the spike train statistics over a broad range of firing rates. Our model can be easily plugged to stimulus processing models, like Linear-nonlinear model or its generalizations, to replace the Poisson spike train hypothesis that is commonly assumed. It estimates the amount of information transmitted much more accurately than Poisson models in retinal recordings. Thanks to its simplicity this model has the potential to explain low variability in other areas.

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arXiv2017

Physical epistatic landscape of antibody binding affinity

Affinity maturation produces antibodies that bind antigens with high specificity by accumulating mutations in the antibody sequence. Mapping out the antibody-antigen affinity landscape can give us insight into the accessible paths during this rapid evolutionary process. By developing a carefully controlled null model for noninteracting mutations, we characterized epistasis in affinity measurements of a large library of antibody variants obtained by Tite-Seq, a recently introduced Deep Mutational Scan method yielding physical values of the binding constant. We show that representing affinity as the binding free energy minimizes epistasis. Yet, we find that epistatically interacting sites contribute substantially to binding. In addition to negative epistasis, we report a large amount of beneficial epistasis, enlarging the space of high-affinity antibodies as well as their mutational accessibility. These properties suggest that the degeneracy of antibody sequences that can bind a given antigen is enhanced by epistasis - an important property for vaccine design.

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arXiv2017

Blindfold learning of an accurate neural metric

The brain has no direct access to physical stimuli, but only to the spiking activity evoked in sensory organs. It is unclear how the brain can structure its representation of the world based on differences between those noisy, correlated responses alone. Here we show how to build a distance map of responses from the structure of the population activity of retinal ganglion cells, allowing for the accurate discrimination of distinct visual stimuli from the retinal response. We introduce the Temporal Restricted Boltzmann Machine to learn the spatiotemporal structure of the population activity, and use this model to define a distance between spike trains. We show that this metric outperforms existing neural distances at discriminating pairs of stimuli that are barely distinguishable. The proposed method provides a generic and biologically plausible way to learn to associate similar stimuli based on their spiking responses, without any other knowledge of these stimuli.

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arXiv2017

Method for identification of condition-associated public antigen receptor sequences

Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type 1 diabetes responsive receptors.

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arXiv2017

Disorder and the neural representation of complex odors: smelling in the real world

Animals smelling in the real world use a small number of receptors to sense a vast number of natural molecular mixtures, and proceed to learn arbitrary associations between odors and valences. Here, we propose a new interpretation of how the architecture of olfactory circuits is adapted to meet these immense complementary challenges. First, the diffuse binding of receptors to many molecules compresses a vast odor space into a tiny receptor space, while preserving similarity. Next, lateral interactions "densify" and decorrelate the response, enhancing robustness to noise. Finally, disordered projections from the periphery to the central brain reconfigure the densely packed information into a format suitable for flexible learning of associations and valences. We test our theory empirically using data from Drosophila. Our theory suggests that the neural processing of olfactory information differs from the other senses in its fundamental use of disorder.

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arXiv2017

IGoR: a tool for high-throughput immune repertoire analysis

High throughput immune repertoire sequencing is promising to lead to new statistical diagnostic tools for medicine and biology. Successful implementations of these methods require a correct characterization, analysis and interpretation of these datasets. We present IGoR -- a new comprehensive tool that takes B or T-cell receptors sequence reads and quantitatively characterizes the statistics of receptor generation from both cDNA and gDNA. It probabilistically annotates sequences and its modular structure can investigate models of increasing biological complexity for different organisms. For B-cells IGoR returns the hypermutation statistics, which we use to reveal co-localization of hypermutations along the sequence. We demonstrate that IGoR outperforms existing tools in accuracy and estimate the sample sizes needed for reliable repertoire characterization.

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arXiv2017

Transitions in optimal adaptive strategies for populations in fluctuating environments

Biological populations are subject to fluctuating environmental conditions. Different adaptive strategies can allow them to cope with these fluctuations: specialization to one particular environmental condition, adoption of a generalist phenotype that compromise between conditions, or population-wise diversification (bet-hedging). Which strategy provides the largest selective advantage in the long run depends on the range of accessible phenotypes and the statistics of the environmental fluctuations. Here, we analyze this problem in a simple mathematical model of population growth. First, we review and extend a graphical method to identify the nature of the optimal strategy when the environmental fluctuations are uncorrelated. Temporal correlations in environmental fluctuations open up new strategies that rely on memory but are mathematically challenging to study: we present here new analytical results to address this challenge. We illustrate our general approach by analyzing optimal adaptive strategies in the presence of trade-offs that constrain the range of accessible phenotypes. Our results extend several previous studies and have applications to a variety of biological phenomena, from antibiotic resistance in bacteria to immune responses in vertebrates.

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arXiv2017

Inferring repeat protein energetics from evolutionary information

Natural protein sequences contain a record of their history. A common constraint in a given protein family is the ability to fold to specific structures, and it has been shown possible to infer the main native ensemble by analyzing covariations in extant sequences. Still, many natural proteins that fold into the same structural topology show different stabilization energies, and these are often related to their physiological behavior. We propose a description for the energetic variation given by sequence modifications in repeat proteins, systems for which the overall problem is simplified by their inherent symmetry. We explicitly account for single amino acid and pair-wise interactions and treat higher order correlations with a single term. We show that the resulting force field can be interpreted with structural detail. We trace the variations in the energetic scores of natural proteins and relate them to their experimental characterization. The resulting energetic force field allows the prediction of the folding free energy change for several mutants, and can be used to generate synthetic sequences that are statistically indistinguishable from the natural counterparts.

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arXiv2017

Population dynamics of immune repertoires

The evolution of the adaptive immune system is characterized by changes in the relative abundances of the B- and T-cell clones that make up its repertoires. To fully capture this evolution, we need to describe the complex dynamics of the response to pathogenic and self-antigenic stimulations, as well as the statistics of novel lymphocyte receptors introduced throughout life. Recent experiments, ranging from high-throughput immune repertoire sequencing to quantification of the response to specific antigens, can help us characterize the effective dynamics of the immune response. Here we describe mathematical models informed by experiments that lead to a picture of clonal competition in a highly stochastic context. We discuss how different types of competition, noise and selection shape the observed clone-size distributions, and contrast them with predictions of a neutral theory of clonal evolution. These mathematical models show that memory and effector immune repertoire evolution is far from neutral, and is driven by the history of the pathogenic environment, while naive repertoire dynamics are consistent with neutral theory and competition in a fixed antigenic environment. Lastly, we investigate the effect of long-term clonal selection on repertoire aging.

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arXiv2017

Closed-loop estimation of retinal network sensitivity reveals signature of efficient coding

According to the theory of efficient coding, sensory systems are adapted to represent natural scenes with high fidelity and at minimal metabolic cost. Testing this hypothesis for sensory structures performing non-linear computations on high dimensional stimuli is still an open challenge. Here we develop a method to characterize the sensitivity of the retinal network to perturbations of a stimulus. Using closed-loop experiments, we explore selectively the space of possible perturbations around a given stimulus. We then show that the response of the retinal population to these small perturbations can be described by a local linear model. Using this model, we computed the sensitivity of the neural response to arbitrary temporal perturbations of the stimulus, and found a peak in the sensitivity as a function of the frequency of the perturbations. Based on a minimal theory of sensory processing, we argue that this peak is set to maximize information transmission. Our approach is relevant to testing the efficient coding hypothesis locally in any context where no reliable encoding model is known.

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