Biology subjects

Nowak, M. A.

Publications and source records attributed to Nowak, M. A..

15 recordsLinked to original sources

bioRxiv2026

An exhaustive map of binary memory-two direct reciprocity over symmetric two-player games

Direct reciprocity, a mechanism for evolution of cooperation, rests on a promise of the future: that the cost of cooperation will be returned in subsequent encounters. Whether reciprocity works is often asked as a question about evolutionary stability: can a population of cooperators resist invasion by mutants that defect? Here we answer this question exhaustively for a large, but finite strategy space projected onto an uncountable infinity of evolutionary games. We take the binary memory-two strategies, in which each of the sixteen possible two-round histories is answered by cooperation or defection up to a small error rate. We work out what every one of them achieves on its own and against every rival, in every symmetric two-player game. Alone, they realise 475 distinct patterns of play carrying 229 distinct cooperation rates. Against each other, a game supports between 299 and 22069 Nash equilibria, that is, resident strategies that no rare mutant can outperform. Efficient strategies, which are those that reach maximum payoff, are present as equilibria at every game, and for 3/8 of games efficient strategies constitute the only equilibria. Those results belong to the limit of a vanishingly small error rate. For any positive error rate the map changes: under 1/4 of all games support no equilibrium, over 3/8 support equilibria but none are efficient, over 1/8 support equilibria and all are efficient, and under 1/4 of games support equilibria of both kinds. Every share quoted here is an exact natural density over the plane of games. The map is the landscape over which any evolutionary dynamics in this strategy space moves.

evolutionary biology↗

bioRxiv2025

Age distinguishes selection from causation in cancer genomes

Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.

cancer biology↗

bioRxiv2025

Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers

The role of extrachromosomal DNA (ecDNA) in lung cancer, particularly in subjects who never smoked (LCINS), remains unclear. Examination of over 1200 whole-genome-sequenced lung cancers identified ecDNA in 18.9% of patients. Recurrent amplification of MDM2 and other oncogenes via ecDNA possibly drives a LCINS subset. Tumors harboring ecDNA showed worse overall survival than tumors harboring other focal amplifications. A strong association with whole-genome doubling suggests most ecDNA reflects genomic instability in treatment-naive lung cancer.

bioinformatics↗

bioRxiv2022

The effect of environmental information on evolution of cooperation in stochastic games

Many human interactions feature the characteristics of social dilemmas where individual actions can have consequences for the group and the environment. The feedback between behavior and environment can be studied with the framework of stochastic games. In stochastic games, the state of the environment can change, depending on the choices made by group members. Past work suggests that such feedback can reinforce cooperative behaviors. In particular, cooperation can evolve in stochastic games even if it is infeasible in each separate repeated game. In stochastic games, participants have an interest in conditioning their strategies on the state of the environment. Yet in many applications, precise information about the state could be scarce. Here, we study how the availability of information (or lack thereof) shapes evolution of cooperation. Already for simple examples of two state games we find surprising effects. In some cases, cooperation is only possible if there is precise information about the state of the environment. In other cases, cooperation is only possible if there is no information about the state of the environment. We systematically analyze all stochastic games of a given complexity class, to determine when receiving information about the environment is better, neutral, or worse for evolution of cooperation.

evolutionary biology↗

bioRxiv2022

Evolutionary safety of death by mutagenesis

Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing "death by mutagenesis" of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of epidemiologically concerning mutated virus progeny. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of virus mutants as a function of the timing of treatment and the immune competence of patients, employing various assumptions about the vulnerability of the viral genome and its potential to generate undesired phenotypes. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against COVID-19. We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment to individuals with a low clearance rate and by designing treatments that lead to a greater increase in mutation rate. We report a simple rule to determine the fold-increase in mutation rate required to obtain evolutionary safety which is also applicable to other pathogen-treatment combinations.

evolutionary biology↗

bioRxiv2020

Variation in genetic relatedness is determined by the aggregate recombination process

The genomic proportion that two relatives share identically by descent--their genetic relatedness-- can vary depending on the history of recombination and segregation in their pedigree. This variation is important in many applications of genetics, including pedigree-based estimation of the genetic variance and heritability of traits, and estimation of pedigree relationships from sequence data. Here, we calculate the variance of genetic relatedness for general pedigree relationships, making no assumptions about the recombination process. For the specific relationships of grandparent-grandoffspring and siblings, the variance of genetic relatedness is a simple decreasing function of [Formula], the average proportion of locus pairs that recombine in meiosis. For general pedigree relationships, the variance of genetic relatedness is likewise the average of some function of pairwise recombination rates. Therefore, features of the aggregate recombination process that affect [Formula] and analogs also affect variance in genetic relatedness. Such features include the number of chromosomes and heterogeneity in their size, and the number of crossovers and their location along chromosomes. Our calculations help to explain several recent observations about variance in genetic relatedness, including that it is reduced by crossover interference (which is known to increase [Formula]). Our methods further allow us to calculate the neutral variance of ancestry among F2s in a hybrid cross, enabling precise statistical inference in F2-based tests for various kinds of selection.

genetics↗

bioRxiv2019

Recombination, variance in genetic relatedness, and selection against introgressed DNA

DNA introgressed from one species into another is typically deleterious at many genomic loci in the recipient species. It is therefore purged by selection over time. Here, we use mathematical modeling and whole-genome simulations to study the influence of recombination on the purging of introgressed DNA. We find that aggregate recombination controls the genome-wide rate of purging in the first few generations after admixture, when purging is most rapid. Aggregate recombination is quantified by [Formula], the average recombination rate across all locus pairs, and analogous metrics. It is influenced by the number of crossovers (i.e., the map length) and their locations along chromosomes, and by the number of chromosomes and heterogeneity in their size. A comparative prediction of our analysis is that species with fewer chromosomes should purge introgressed DNA more profoundly, and therefore should exhibit a weaker genomic signal of historical introgression. With regard to patterns across the genome, we show that, in heterogametic species with autosomal recombination in both sexes, more purging is expected on sex chromosomes than on autosomes, all else equal. The opposite prediction holds for species without autosomal recombination in the heterogametic sex. Finally, we show that positive genomic correlations between local recombination rate and introgressed ancestry, as recently observed in several taxa, are likely driven not by recombinations effect in unlinking neutral from deleterious introgressed alleles, but rather by its effect on the rate of purging of the deleterious alleles themselves. Note on this versionAn earlier version of this manuscript had two parts: (1) Calculations of the variance of genetic relatedness between individuals with particular pedigree relationships, taking into account the randomness of recombination and segregation in their pedigree. (2) An investigation of the rate of purging of introgressed DNA following admixture, based in part on results from part (1). Part (1) has since been published as Veller et al. (2020). The present manuscript has been reconfigured to focus on part (2).

evolutionary biology↗

bioRxiv2019

Evolutionary Origins of Recurrent Pancreatic Cancer

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

cancer biology↗

bioRxiv2019

Observing changes in human functioning during induced sleep deficiency and recovery periods

The duration of sleep, wakefulness and dynamic changes in human performance are determined by neural and genetic mechanisms. Sleep deprivation and chronic restriction of sleep cause perturbations of circadian rhythmicity and degradation of waking alertness as reflected in attention, cognitive efficiency and memory. In this work we report on multiple neurobehavioral correlates of sleep loss in healthy adults in an unprecedented study comprising 21 consecutive days divided into periods of 4 days of regular life (a baseline), 10 days of chronic partial sleep restriction and 7 days of recovery. Throughout the whole experiment we continuously measured the spontaneous locomotor activity by means of actigraphy with 1-minute resolution in two acquisition modes (frequency and intensity of movement). Moreover, on daily basis the subjects were undergoing EEG measurements (64-electrodes with 500 Hz sampling frequency): resting state with eyes open and closed (RS; 8 minutes long each) followed by Stroop task (ST; 22 minutes). Altogether we analyzed actigraphy (distributions of rest and activity durations), behavioral measures (accuracy and reaction times from Stroop task) and EEG (amplitudes, latencies and scalp maps of event-related potentials from Stroop task and power spectra from resting states). The actigraphy measures clearly indicate rapid changes after sleep restriction onset, confirming our former investigations -- the novel insight is a slow and incomplete relaxation to the original locomotor behavior. The pattern of partial recovery appears also in accuracy (in ST) and power of delta rhythm (in RS). The impact of sleep loss is also evident in reaction times (in ST), yet followed by complete recovery, and finally in ERP amplitudes and latencies, which however did not return to the baseline at all. The results indicate that short periods (a few days) of recovery sleep subsequent to prolonged periods of sleep restriction are overall insufficient to recover fully.

neuroscience↗

bioRxiv2018

Novel cytokine interactions identified during perturbed hematopoiesis

Hematopoiesis is a dynamic process involving the up- and down-regulation of genes, as well as feed-back loops that stimulate or suppress circulating cytokine concentrations. More complete pictures of the gene regulatory networks that control the production of the blood system have emerged with the advent of single-cell sequencing techniques and refinements to the capabilities of immunoassays. However, information about the regulatory networks of cytokines is still lacking. A novel mathematical technique (convergent cross-mapping, or CCM) allows for the extraction of causal relationships from data, which is of crucial importance for understanding these networks. To reconstruct the cytokine networks within the hematopoietic system we measured the concentrations of 62 cytokines, platelets, and thrombopoietin from an individual with cyclic thrombocytopenia (regular oscillations in the megakaryocytes and platelets) over 84 days. Using CCM, we identified 61 previously unreported cytokine relationships. Our approach is the first broad-scale investigation into causal relationships between cytokines in the blood and suggests a new paradigm for understanding how dynamic regulation occurs during hematopoiesis.

immunology↗

bioRxiv2018

Selection for synchronized cell division in simple multicellular organisms

The evolution of multicellularity was a major transition in the history of life on earth. Conditions under which multicellularity is favored have been studied theoretically and experimentally. But since the construction of a multicellular organism requires multiple rounds of cell division, a natural question is whether these cell divisions should be synchronous or not. We study a simple population model in which there compete simple multicellular organisms that grow either by synchronous or asynchronous cell divisions. We demonstrate that natural selection can act differently on synchronous and asynchronous cell division, and we offer intuition for why these phenotypes are generally not neutral variants of each other.

evolutionary biology↗

bioRxiv2017

Current CRISPR gene drive systems are likely to be highly invasive in wild populations

Recent reports have suggested that CRISPR-based gene drives are unlikely to invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption. We show that although resistance prevents drive systems from spreading to fixation in large populations, even the least effective systems reported to date are highly invasive. Releasing a small number of organisms often causes invasion of the local population, followed by invasion of additional populations connected by very low gene flow rates. Examining the effects of mitigating factors including standing variation, inbreeding, and family size revealed that none of these prevent invasion in realistic scenarios. Highly effective drive systems are predicted to be even more invasive. Contrary to the National Academies report on gene drive, our results suggest that standard drive systems should not be developed nor field-tested in regions harboring the host organism.

synthetic biology↗

bioRxiv2017

Drift-Induced Selection Between Male And Female Heterogamety

Evolutionary transitions between male and female heterogamety are common in both vertebrates and invertebrates. Theoretical studies of these transitions have found that, when all genotypes are equally fit, continuous paths of intermediate equilibria link the two sex chromosome systems. This observation has led to a belief that neutral evolution along these paths can drive transitions, and that arbitrarily small fitness differences among sex chromosome genotypes can determine the system to which evolution leads. Here, we study stochastic evolutionary dynamics along these equilibrium paths. We find non-neutrality, both in transitions retaining the ancestral pair of sex chromosomes and in those creating a new pair. In fact, substitution rates are strongly biased in favor of dominant sex determining chromosomes, which fix with higher probabilities than mutations of no effect. Using diffusion approximations, we show that this non-neutrality is a result of drift-induced selection operating at every point along the equilibrium paths: stochastic jumps off the paths return, on average, with a directional bias in favor of the dominant segregating sex chromosome. Our results offer novel explanations for the ubiquity of transitions between male and female heterogamety and the preponderance of dominant major sex determining genes.

evolutionary biology↗

bioRxiv2017

The evolution of queen control over worker reproduction in the social Hymenoptera

A trademark of eusocial insect species is reproductive division of labor, in which workers forego their own reproduction while the queen produces almost all offspring. The presence of the queen is key for maintaining social harmony, but the specific role of the queen in the evolution of eusociality remains unclear. A long-discussed scenario is that a queen either behaviorally or chemically sterilizes her workers. However, the demographic and ecological conditions that enable such manipulation are unknown. Accordingly, we propose a simple model of evolutionary dynamics that is based on haplodiploid genetics. We consider a mutation that acts in a queen, causing her to control the reproductive behavior of her workers. Our mathematical analysis yields precise conditions for the evolutionary emergence and stability of queen-induced worker sterility. These conditions do not depend on the queen's mating frequency. Moreover, we find that queen control is always established if it increases colony reproductive efficiency and can evolve even if it decreases colony efficiency. We further outline the conditions under which queen control is evolutionarily stable against invasion by mutant, reproductive workers.

evolutionary biology↗

bioRxiv2016

An exactly solvable, spatial model of mutation accumulation in cancer

One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model.

cancer biology↗