Biology subjects

Doumic, M.

Publications and source records attributed to Doumic, M..

7 recordsLinked to original sources

bioRxiv2026

Telomere dynamics parameters inferred from mathematical modeling of telomere length distribution

Telomeres, repeated sequences located at the ends of linear chromosomes, are essential for genome integrity. As these regions are subject to dynamics of shortening and lengthening by telomerase, they exhibit length heterogeneity. Telomere length is thus best represented by an entire distribution rather than by a single value. Long-read sequencing technologies now allow us to experimentally access this distribution at high resolution. Our working hypothesis posits that this distribution encodes information that relates to the biochemical mechanisms underlying telomere length dynamics. Here, to numerically infer the biochemical parameters that control telomere shortening and elongation by telomerase, we developed a mathematical model that we fit on long-read-sequencing-derived telomere length distributions of Saccharomyces cerevisiae. We prove that in our model, telomere length can be mathematically represented as an ergodic Markov chain and we provide an explicit expression of the steady-state distribution. We show that the biochemical parameters can be uniquely inferred from the distribution, which we verify on synthetic data with known ground truth parameters. Using experimental telomere length distributions of wild-type and mutants of telomere regulators, we find that our pipeline of parameter inference yields biologically relevant values. We then fit the model to the telomere length distribution of 66 natural yeast strains to reveal the diversity of telomere length regulation parameters. Furthermore, we demonstrate that individual chromosome extremities can sometimes be associated with distinct regulation parameters. Overall, our mathematical model and computational pipeline represent a powerful approach to estimate biochemical parameters affecting telomere length regulation.

genomics↗

bioRxiv2026

Acute Smurf mortality and inter-phase dependence in Drosophila and mice identified through comprehensive modelling and statistical analysis of two-phase ageing

Ageing is traditionally conceived as a continuous process of progressive physiological decline. However, recent evidence across species suggests that ageing may instead proceed through distinct phases. Using state-of-the-art statistical methods, we develop a rigorous analysis of longitudinal survival data from 1,159 individually tracked female Drosophila melanogaster. This data-driven analysis leads us to introduce a new parametric model of transition rates within the two-phase ageing framework. Flies were monitored using the Smurf assay, which detects increased intestinal permeability through leakage of an ingested blue dye, and is a strong biological marker of ageing. The Smurf phenotype identifies a sharp transition from a non-Smurf state to a Smurf state that precedes death. Our results yield three key findings. First, the Smurf transition rate follows a Gompertz-Makeham law, increasing exponentially with age. Second, contrary to previous constant-rate assumptions, newly transitioned Smurf flies exhibit remarkably high mortality - approximately 40% die within 24 hours - followed by an exponential decline in death rate that stabilises to a lower constant baseline. Third, we identified a mild but statistically significant negative dependence between time spent non-Smurf and subsequent Smurf lifespan. Our best-fit model captures a potential bimodal nature of mortality curves using simple, biologically interpretable functions. Validation using data from two mouse strains confirms the broader applicability of this framework. These results establish a quantitative foundation for the two-phase ageing paradigm and highlight a critical period of vulnerability immediately following the physiological transition to frailty.

systems biology↗

bioRxiv2025

Deciphering the Replication-Division Coordination in E. coli: A Unified Mathematical framework for Systematic Model Comparison

Despite extensive research, the quantitative principles that govern the coordination between DNA replication and cell division in bacteria remain debated. Multiple theoretical models have been proposed, some postulating that a single regulatory process is sufficient to ensure replication-division coordination, while others argue that two concurrent processes are required for robust control. In this work, we develop a unifying mathematical framework within which models can be consistently formulated, qualitatively analysed and quantitatively compared. This framework also allows us to propose a new double-process model. Through theoretical analysis, we establish the necessary and sufficient conditions under which single-process models can reproduce physiological cell behaviours. Beyond the correlation-based analyses extensively used to date, we further demonstrate within a comprehensive statistical framework that double-process models more accurately recapitulate experimental data across all growth conditions. Specifically, the new model we propose robustly captures the replication-division coordination in every growth regime, thereby providing a foundation for future mechanistic studies. Author SummaryHow bacteria regulate their cell size and ensure complete chromosome replication before division remains only partly understood, posing a fundamental question. A key challenge is understanding how bacterial cells reliably distribute their genetic material to daughter cells while managing randomness in division timing, especially since DNA replication is often initiated in earlier generations. Over the past decade, several models have been developed to describe the coordination of DNA replication and cell division in Escherichia coli, combining different mechanisms and levels of complexity. These models have mainly been evaluated through correlation analysis between cell cycle parameters, such as the size at which bacteria divide or initiate DNA replication. However, such analyses depend on strong underlying assumptions that are not always met by the experimental data. Here, we present a general framework that systematically integrates multiple models, allowing both qualitative analysis and quantitative comparison without relying on correlations. Our work concludes that under all growth conditions, E. coli cells most likely divide only after meeting two combined requirements: adding a critical size since birth and a critical size since the initiation of DNA replication.

cell biology↗

bioRxiv2025

The shortest telomere in telomerase-negative cells triggers replicative senescence at a critical threshold length and also fuels genomic instability

In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we developed a system in Saccharomyces cerevisiae to generate and track telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival.

molecular biology↗

bioRxiv2021

Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae

BackgroundTelomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. ResultsHere, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. ConclusionsReplicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

bioinformatics↗

bioRxiv2019

Quaternary structural convergence and structural diversification of prion assemblies at the early replication stage

Aggregation of misfolded forms from host-encoded proteins is key to the pathogenesis of a number of neurodegenerative disorders, including prion diseases, Alzheimers disease and Parkinsons disease. In prion diseases, the cellular prion protein PrPC can misfold into PrPSc and auto-organize into conformationally distinct assemblies or strains. A plethora of observations reports the existence of PrPSc structural heterogeneity within prion strains, suggesting the emergence and coevolution of structurally distinct PrPSc assemblies during prion replication in controlled environment. Such PrPSc diversification processes remain poorly understood. Although central to prion host-adaptation, structural diversification of PrPSc assemblies is also a key issue for the formation of PrP conformers involved in neuronal injury. Here, we characterized the evolution of the PrPSc quaternary structure during prion replication in vivo and in bona fide cell-free amplification assays. Regardless of the strain studied, the early replication stage conduced to the preferential formation of small PrPSc oligomers, thus highlighting a quaternary structural convergence phenomenon. Their evolutionary kinetics revealed the existence of a PrPC-dependent secondary templating pathway in concert with a structural rearrangement. This secondary templating pathway provides, for the first time, a mechanistic explanation for prion structural diversification during replication, a key determinant for prion adaptation on further transmission, including to other host species. The uncovered processes are also key for a better understanding of the accumulation mechanisms of other misfolded assemblies believed to propagate by a prion-like process.

biochemistry↗

bioRxiv2018

The Division of Amyloid Fibrils

The division of amyloid protein fibrils is required for the propagation of the amyloid state, and is an important contributor to their stability, pathogenicity and normal function. Here, we combine kinetic nano-scale imaging experiments with analysis of a mathematical model to resolve and compare the division stability of amyloid fibrils. Our theoretical results show that the division of any type of filament is uniquely described by a set of three characteristic properties, resulting in convergence to self-similar length distributions distinct to each fibril type and conditions applied. By applying these results to profile the dynamical stability towards breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from alpha-synuclein compared with non-disease associated model amyloid, the former showing lowered intrinsic stability towards breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments intrinsic dynamic stabilities, which are key to unravelling their toxic and infectious potentials.

biophysics↗