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bioRxiv2018

miRNA analysis with Prost! reveals evolutionary conservation of organ-enriched expression and post-transcriptional modifications in three-spined stickleback and zebrafish

MicroRNAs (miRNAs) can have tissue-specific expression and functions; they can originate from dedicated miRNA genes, from non-canonical miRNA genes, or from mirror-miRNA genes and can also experience post-transcriptional variations. It remains unclear, however, which mechanisms of miRNA production or modification are tissue-specific and the extent of their evolutionary conservation. To address these issues, we developed the software Prost! (PRocessing Of Short Transcripts), which, among other features, allows accurate quantification of mature miRNAs, takes into account post-transcriptional processing, such as nucleotide editing, and helps identify mirror-miRNAs. Here, we applied Prost! to annotate and analyze miRNAs in three-spined stickleback (Gasterosteus aculeatus), a model fish for evolutionary biology reported to have a miRNome larger than most teleost fish. Zebrafish (Danio rerio), a distantly related teleost with a well-known miRNome, served as comparator. Despite reports suggesting that stickleback had a large miRNome, results showed that stickleback has 277 evolutionary-conserved mir genes and 366 unique mature miRNAs (excluding mir430 gene replicates and the vaultRNA-derived mir733), similar to zebrafish. In addition, small RNA sequencing data from brain, heart, testis, and ovary in both stickleback and zebrafish identified suites of mature miRNAs that display organ-specific enrichment, which is, for many miRNAs, evolutionarily-conserved. These data also supported the hypothesis that evolutionarily-conserved, organ-specific mechanisms regulate miRNA post-transcriptional variations. In both stickleback and zebrafish, miR2188-5p was edited frequently with similar nucleotide editing patterns in the seed sequence in various tissues, and the editing rate was organ-specific with higher editing in the brain. In summary, Prost! is a critical new tool to identify and understand small RNAs and can help clarify a species miRNA biology, as shown here for an important fish model for the evolution of developmental mechanisms, and can provide insight into organ-specific expression and evolutionary-conserved miRNA post-transcriptional mechanisms.

molecular biology↗

bioRxiv2024

Co-evolution of Yeast and Microalga: Identification of mutations that improve cooperativity

Laboratory-based evolution has long been successfully implemented for the generation of desired phenotypes in microbial strain development. The approach also provides insights into evolutionary mechanisms and adaptive molecular strategies which may be too complex to unravel in natural environments. The selection pressure in most of these approaches are physical or chemical factors or stressors, and only a few projects have attempted to use dynamic biotic selection pressures as a driver of evolution. Here we investigate the formation of novel cooperative phenotypes between the yeast Saccharomyces cerevisiae and the microalga Chlorella sorokiniana. A synthetic ecology approach based on the cross-feeding of carbon and nitrogen was used to establish an obligate mutualism between these species which allowed for prolonged physical contact in a continuous co-culture system over 100 generations. Comparative genomic analysis of co-evolved yeast strains identified several potentially high impact Single Nucleotide Polymorphisms. Of these, two genes ETP1 and GAT1, were found to synergistically contribute to the cooperative phenotype between yeast and microalgae These genes are involved in carbon (ETP1) and nitrogen catabolite (GAT1) repression with ETP1 encoding a protein of unknown function, but implicated in ethanol tolerance and control of Hxt3p, while GAT1 encodes a regulator of nitrogen catabolite repression. CRISPR generated null mutants of the parental (ancestral) yeast strain with either ETP1, GAT1 or both genes deleted, were shown to mimic the co-evolved phenotype with improved cooperativity observed when paired with Chlorella sorokiniana suggesting a possible role of these genes in the establishment of mutualisms between yeast and microalgae. ImportanceMultispecies cultures have tremendous biotechnological potential but are difficult to control and show unpredictable population dynamics. This research aims to comprehensively characterise the behaviour and attributes of co-cultured microbial species, with the aim of optimising their combined functionality in a targeted manner. Taken together, our results demonstrate the importance and efficacy of thoughtfully integrating biotic selection pressures into strain development projects. The data also provide insights into specific molecular adaptations that favour cooperative behaviour between species. The co-evolutionary dynamics between Saccharomyces cerevisiae and other microbial species hold immense promise for unlocking novel insights into evolutionary biology, biotechnological applications, and our understanding of complex microbiological systems. Finally, the molecular characterisation of ecosystem-relevant traits provides significant impetus to the annotation of microbial genomes within an evolutionary relevant, multispecies context.

microbiology↗

bioRxiv2026

Ancestral sequence reconstruction using generative models

Ancestral sequence reconstruction (ASR) is a foundational task in evolutionary biology, providing insights into the molecular past and guiding studies of protein function and adaptation. Conventional ASR methods rely on a multiple sequence alignment (MSA), a phylogenetic tree, and an evolutionary model. However, the underlying alignments and trees are often uncertain, and existing models typically focus on substitutions and do not explicitly account for insertion-deletion (indel) processes. Here, we introduce BetaReconstruct, a novel generative approach to ASR that harnesses recent advances in natural language processing (NLP) and hybrid transformer architectures. Our model was initially trained on large-scale simulated datasets with gold-standard ancestral sequences and subsequently on real-world protein sequences. The reconstruction requires neither MSAs nor phylogenetic trees. We demonstrate that BetaReconstruct generalizes robustly across diverse evolutionary scenarios and reconstructs ancestral sequences more accurately than maximum-likelihood-based pipelines. We additionally provide evidence that the generative-model ASR approach is also more accurate when analyzing empirical datasets. This work provides a scalable, alignment-free strategy for ASR and highlights the ability of data-driven models to capture evolutionary signals beyond the reach of traditional methods.

bioinformatics↗

bioRxiv2020

Transcriptome analysis reveals evolutionary co-option of neural development and signaling genes for the wing pigmentation pattern of the polka-dotted fruit fly.

How evolutionary novelties have arisen is one of the central questions in evolutionary biology. Pre-existing gene regulatory networks or signaling pathways have been shown to be co-opted for building novel traits in several organisms. However, the structure of entire gene regulatory networks and evolutionary events of gene co-option for emergence of a novel trait are poorly understood. In this study, we used a novel wing pigmentation pattern of the polka-dotted fruit fly, and identified the complete set of genes for pigmentation pattern formation by de novo genome sequencing and transcriptome analyses. In pigmentation areas of wings, 151 genes were positively or negatively regulated by wingless, a master regulator of wing pigmentation. Genes for neural development, Wnt signaling, Dpp signaling, Zinc finger transcription factors, and effectors (such as enzymes) for melanin pigmentation were included among these 151 genes. None of the known regulatory genes that regulate pigmentation pattern formation in other fruit fly species were included. Our results suggest that the novel pigmentation pattern of the polka-dotted fruit fly emerged through multi-step co-options of multiple gene regulatory networks, signaling pathways, and effector genes, rather than recruitment of one large gene circuit.

developmental biology↗

bioRxiv2017

Improved genome assembly and annotation for the rock pigeon (Columba livia)

The domestic rock pigeon (Columba livia) is among the most widely distributed and phenotypically diverse avian species. This species is broadly studied in ecology, genetics, physiology, behavior, and evolutionary biology, and has recently emerged as a model for understanding the molecular basis of anatomical diversity, the magnetic sense, and other key aspects of avian biology. Here we report an update to the C. livia genome reference assembly and gene annotation dataset. Greatly increased scaffold lengths in the updated reference assembly, along with an updated annotation set, provide improved tools for evolutionary and functional genetic studies of the pigeon, and for comparative avian genomics in general.

genomics↗

bioRxiv2025

The first chromosome-scale Dugesia genomes shed light on structural rearrangements and genome size evolution in flatworms

AbstractHigh-quality, chromosome-scale genomes are crucial for understanding biological processes, yet many metazoan lineages, including most Lophotrochozoa, remain underrepresented in genome databases. Among these, planarians (Platyhelminthes, Tricladida), particularly Dugesia, are a globally distributed and phenotypically diverse group that has become an important model in evolutionary biology, notably for investigating the genetic effects of agametic asexuality. However, the lack of chromosome-scale assemblies has limited progress. Here, we present the first chromosome-scale genomes of four Western Mediterranean Dugesia species, displaying the first intra- and intergeneric comparisons. Comparison with the regeneration model organism Schmidtea mediterranea, rejects a whole-genome duplication as the cause of differences in chromosomal number and genome size between genera. Instead, Dugesia shows extensive lineage-specific and differential expansions of DNA transposable elements, likely contributing to genome size variation during diversification. Despite differences in the dynamics of structural genome rearrangements observed between genera, both groups lack the conservation of ancestral metazoan linkage groups, supporting the idea that genome structural instability is a key feature of flatworm genome evolution. Our newly generated genomic resources and findings offer vital insights into the genetic basis of diversification and establish Dugesia as a valuable model for studying metazoan genome dynamics, including the evolution of alternative reproductive systems.

genomics↗

bioRxiv2019

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

The biology of how faces are built and come to differ from one another is complex. Discovering the genes that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and X-chromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTLs peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.\n\nAuthor SummaryThe mammalian face is a complex structure serving many functions. We studied the genetic basis for facial skeletal diversity in a large sample of mice from an experimental population designed for the study of complex traits. We quantified the contribution of genetic variation to variation in three-dimensional facial shape across more than 55,000 genetic markers spread throughout the mouse genome. We found 37 genetic regions which are very likely to contribute to differences in facial shape. We then conducted a more detailed analysis of the genetic regions associated with the most variable aspects of facial shape. For these regions, a disproportionately large number of genes are known to be important to growth and to skeletal and facial development. The magnitude of these genetic contributions to differences in facial shape are consistently small. Our results therefore support the notion that facial skeletal diversity is influenced by many genes of small effect, but that some of these small effects may be related to genes that are fundamental to skeletal and facial development.

genetics↗

bioRxiv2022

Differential sensory and immune gene evolution in sea turtles with contrasting demographic and life histories

Sea turtles represent an ancient lineage of marine vertebrates that evolved from terrestrial ancestors over 100 MYA, yet the genomic basis of the unique physiological and ecological traits enabling these species to thrive in diverse marine habitats remains largely unknown. Additionally, many populations have drastically declined due to anthropogenic activities over the past two centuries, and their recovery is a high global conservation priority. We generated and analyzed high-quality reference genomes for the leatherback (Dermochelys coriacea) and green (Chelonia mydas) turtles, representing the two extant sea turtle families. These genomes are highly syntenic and homologous, but localized regions of non-collinearity were associated with higher copy numbers of immune, zinc-finger, and olfactory receptor (OR) genes in green turtles, with ORs related to waterborne odorants greatly expanded in green turtles. Our findings suggest that divergent evolution of these key gene families may underlie immunological and sensory adaptations assisting navigation, occupancy of neritic versus pelagic environments, and diet specialization. Reduced collinearity was especially prevalent in microchromosomes, with greater gene content, heterozygosity, and genetic distances between species, supporting their critical role in vertebrate evolutionary adaptation. Finally, diversity and demographic histories starkly contrasted between species, indicating that leatherback turtles have had a low yet stable effective population size, exhibit extremely low diversity compared to other reptiles, and harbor a higher genetic load compared to green turtles, reinforcing concern over their persistence under future climate scenarios. These genomes provide invaluable resources for advancing our understanding of evolution and conservation best practices in an imperiled vertebrate lineage. Statement of significanceSea turtle populations have undergone recent global declines. We analyzed de novo assembled genomes for both extant sea turtle families through the Vertebrate Genomes Project to inform their conservation and evolutionary biology. These highly conserved genomes were differentiated by localized gene-rich regions of divergence, particularly within microchromosomes, suggesting that these genomic elements play key functional roles in the evolution of sea turtles and possibly other vertebrates. We further demonstrate that dissimilar evolutionary histories impact standing genomic diversity and genetic load, and are critical to consider when using these metrics to assess adaptive potential and extinction risk. Our results also demonstrate how reference genome quality impacts inferences of comparative and conservation genomics analyses that need to be considered in their application.

genomics↗

bioRxiv2016

Maximizing ecological and evolutionary insight from bisulfite sequencing data sets

The role of DNA methylation in development, divergence, and the response to environmental stimuli is of substantial interest in ecology and evolutionary biology. Measuring genome-wide DNA methylation is increasingly feasible using sodium bisulfite sequencing. Here, we analyze simulated and published data sets to demonstrate how effect size, kinship/population structure, taxonomic differences, and cell type heterogeneity influence the power to detect differential methylation in bisulfite sequencing data sets. Our results reveal that the effect sizes typical of evolutionary and ecological studies are modest, and will thus require data sets larger than those currently in common use. Additionally, our findings emphasize that statistical approaches that ignore the properties of bisulfite sequencing data (e.g., its count-based nature) or key sources of variance in natural populations (e.g., population structure or cell type heterogeneity) often produce false negatives or false positives, thus leading to incorrect biological conclusions. Finally, we provide recommendations for handling common issues that arise in bisulfite sequencing analyses and a freely available R Shiny application for simulating and performing power analyses on bisulfite sequencing data. This app, available at www.tung-lab.org/protocols-and-software.html, allows users to explore the effects of sequencing depth, sample size, population structure, and expected effect size, tailored to their own system.

genomics↗

bioRxiv2019

A common molecular basis to the convergent evolution of the selfing syndrome in Capsella

Whether, and to what extent, phenotypic evolution follows predictable genetic paths, remains an important question in evolutionary biology. Convergent evolution of similar characters provides a unique opportunity to address this question. The transition to selfing and the associated changes in flower morphology are among the most prominent examples of repeated evolution in plants. Yet, to date no studies have directly compared the extent of similarities between convergent adaptations to selfing. In this study, we take advantage of the independent transitions to self-fertilization in the genus Capsella to test the existence of genetic and developmental constraints imposed on flower evolution in the context of the selfing syndrome. While C. rubella and C. orientalis have emerged independently, both have evolved almost identical flower characters. Not only the evolutionary outcome is identical but, in both cases, the same developmental strategies underlie the convergent reduction of flower size. This has been associated with convergent evolution of gene-expression changes. The transcriptomic changes common to both selfing lineages are enriched in genes with low-network connectivity and with organ-specific expression patterns. Comparative genetic mapping also indicates that, at least in the case of petal size evolution, these similarities are largely caused by mutations at the same loci. Together, these results suggest that the limited availability of low-pleiotropy paths predetermine closely related species to similar evolutionary outcomes.

plant biology↗

bioRxiv2026

A fast neutron mutant resource for Ipomoea purpurea reveals dose-dependent genomic and phenotypic variation

A central goal in evolutionary biology is to understand the genomic basis of phenotypic traits, yet this pursuit is often constrained by a lack of accessible phenotypic and genetic variation, particularly in non-model organisms. Fast neutron irradiation offers a powerful approach for generating such variation, as it does not require prior genomic resources, established transformation systems, or reference mutant collections. Here, we describe the development and characterization of the first fast neutron mutant library in Ipomoea purpurea (common morning glory), a noxious agricultural weed and established model system in evolutionary ecology. We exposed an I. purpurea reference genotype to three levels of irradiation and developed 1,043 lines third generation lines and characterized the phenotypic and genetic variation in a subset of 200. Phenotypic screens identified seven mutant lines exhibiting eleven distinct phenotypes, and revealed higher phenotypic variance for anther-stigma distance, flower number, and pollen count relative to a non-irradiated control line. We further identified genetic variation across eight phenotypic traits among the mutant lines. Together, these results show that fast neutron mutagenesis generates novel phenotypic and genetic variation in ecologically relevant traits, offering the research community a new genomic resource for an established model in evolutionary ecology.

plant biology↗

bioRxiv2026

Clade dynamics support an early origin of crown eukaryotes

The timing of the last eukaryotic common ancestor (LECA) remains a fundamental question in evolutionary biology and palaeontology. Unambiguous eukaryotic-grade fossils appear from 1780 Ma, but no crown-group supergroups are confidently identified before the end of the Mesoproterozoic (ca. 1050 Ma). The late LECA hypothesis suggests that this absence of crown-assignable fossils and biosignatures implies a late Mesoproterozoic origin of the crown. Here we show that this hypothesis is incompatible with the evolutionary dynamics of the eukaryote clade, even under the limited constraints of the fossil record. Studying stem-crown dynamics based on a birth-death model, we show that a late crown age requires diversification rates well below the minimum rate needed to generate observed living eukaryote diversity (~2.5 - 10 million species) for any plausible total group age. Our results suggest that only an early LECA can bridge evolutionary dynamics with the eukaryotic-grade fossil record, the living diversity, and the molecular clock estimates. Based on these constraints, we suggest a feasible minimum age estimate for LECA of ca. 1696 Ma, supported by current fossil evidence and supporting molecular clock estimates. These results also provide a fossil-testable prediction: crown-group eukaryotes likely exist in early Mesoproterozoic assemblages, albeit undetected with current morphology-based approaches.

paleontology↗

bioRxiv2024

Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2

The Covid-19 pandemic showcases a coevolutionary race between the human immune system and SARS-CoV-2, mirroring the Red Queen hypothesis of evolutionary biology. The immune system generates neutralizing antibodies targeting the SARS-CoV-2 spike proteins receptor binding domain (RBD), crucial for host cell invasion, while the virus evolves to evade antibody recognition. Here, we establish a synthetic coevolution system combining high-throughput screening of antibody and RBD variant libraries with protein mutagenesis, surface display, and deep sequencing. Additionally, we train a protein language machine learning model that predicts antibody escape to RBD variants. Synthetic coevolution reveals antagonistic and compensatory mutational trajectories of neutralizing antibodies and SARS-CoV-2 variants, enhancing the understanding of this evolutionary conflict.

synthetic biology↗

bioRxiv2025

Genomes of ancient asexual mites appear streamlined in their architecture

The long-term persistence of obligate asexual lineages represents one of the most enduring and critical paradoxes in evolutionary biology. Sexual reproduction, through meiotic recombination and segregation, enables the efficient removal of deleterious mutations and facilitates rapid adaptation to shifting environmental pressures. Lineages that lose sex are therefore classically predicted to experience genomic decay and face rapid extinction. Oribatid mites (Acari, Sarcoptiformes) represent a unique system for testing these predictions, as they feature multiple, ancient, and independent transitions to asexuality, providing a natural experiment on the evolutionary fate of asexual genomes. We compared four sets of sister sexual and asexual species using high-quality nuclear genome assemblies to investigate the genomic consequences of long-term asexuality. Our study revealed a profound, reproductive-mode-dependent dichotomy in the evolution of genome architecture. Contrary to their expected genomic decay, asexual species have mostly streamlined genomes with less novel genes than their sexual sister species. In contrast, sexual species have acquired genetic innovations, encompassing both gene and transposable element content. These results challenge classical expectations of genomic deterioration in asexual species and might explain the long-term evolutionary persistence of oribatid mites.

genomics↗

bioRxiv2025

Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction

The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15BR658C genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B*PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in Ppp1r15bR658C mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions--including Down syndrome, Alzheimers disease and aging--but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.

neuroscience↗

bioRxiv2020

Laboratory evolution of multiple E. coli strains reveals unifying principles of adaptation but diversity in driving genotypes

Fitness landscapes are a central concept in evolutionary biology and have been thoroughly detailed in terms of genotypes. However, our understanding of the selected metabolic and gene expression adaptations, and their dependence on genetic background, remains limited. Here, we reveal multi-scale adaptation principles in the E. coli species by taking multi-omics measurements of six different strains throughout their adaptive evolution to glucose minimal media. Statistics and matrix factorization is applied to yield four key results. First, analysis of the metabolic and physiological data shows evolutionary convergence in growth rate, glucose uptake rate, glycolytic ATP and NADH production but divergence in NADPH production strategies. Second, factorization-based analysis of the transcriptome revealed six conserved transcriptomic adaptations describing increased expression of ribosome and amino acid biosynthetic genes and decreased expression of stress response and structural genes. Third, correlation analysis identifies five tradeoffs underlying the transcriptomic profiles. Fourth, statistical tests leveraging ALE design identify four mutation-flux correlates and eight mutation-transcriptomic correlates that link mutations to systems level adaptation principles. Our total results reveal the dominant metabolic and regulatory constraints governing E. coli growth adaptation that either distinguish strains or are conserved principles.

systems biology↗

bioRxiv2026

Zero-shot design of a de novo metalloenzyme

The de novo design of enzymes remains a central challenge, requiring consideration of catalytic mechanism and optimization across biochemical and biophysical criteria. Here we present dEVA (design by EVolutionary Algorithm), a multi-objective protein design framework built on principles drawn from evolutionary biology. We apply dEVA to the zero-shot, de novo design of metalloenzymes by optimizing the coordination sphere of catalytic metals. We characterize a bizinc metalloenzyme that exhibits promiscuous hydrolytic activity towards both phosphomonoesters and phosphodiesters. This design achieves a rate enhancement ((kcat/KM)/kw) up to 3 x 1013, comparable to characterized natural phosphatases. dEVA offers a general and modular strategy for the programmable design of protein function without dependence on natural templates or evolutionary information.

biochemistry↗

bioRxiv2025

Replication rate-information storage trade-off shapes genome architecture across domains

Genome size varies widely among organisms, from compact genomes of bacteria to vast and complex genomes of eukaryotes. In this study, we theoretically identify the evolutionary pressures that may have driven this divergence in genome size. We use a parameter-free model to study genome size evolution under selection pressure to minimize replication time and maximize information storage capacity. We substantiate this choice by demonstrating a correlation between replication time and genome size using literature data. We show that bacteria tend to reduce genome size, constrained by a single replication origin, while eukaryotes expand their genomes by incorporating multiple replication origins. We propose a connection between genome size and cellular energetics, suggesting that endosymbiotic organelles, mitochondria and chloroplasts, evolutionarily regulate the number of replication origins, thereby influencing genome size in eukaryotes. We substantiate this claim by showing a correlation between organelle count and genome size data. We argue that nucleotide skews, present in nearly all genomes studied, and are used to identify replication origins, directly influence DNA unzipping kinetics, and hence its replication time. This connection enables us to derive nearly universal observations, such as Chargaffs second parity rule and replichore symmetrization, as adaptive consequences. We argue that high skews lead to faster replication, and substantiate it by showing a correlation between skews and replication speed in bacteria. The model reproduces more evolutionary genomic observations, such as a general preference for deletions over insertions across domains, and elongation and high variance of genome size under reduced selection pressure for replication rate, an integral component of C-value paradox. We highlight the possibility of regulation of the firing of latent replication origins in response to cues from the extracellular environment, leading to the regulation of cell cycle rates in multicellular eukaryotes. Significance StatementUnderstanding the forces shaping genome architecture is a long-standing challenge in evolutionary biology. Our study demonstrates that the balance between replication speed, influenced by nucleotide skews, and information storage, constrained by cellular energetics, drives the divergence in genome size between bacteria and eukaryotes. By quantifying selection pressure as the ratio of replication time to genomic information storage capacity, we show that this pressure enforces adaptive constraints, giving rise to observed features such as symmetric replichores and Chargaffs second parity rule. These insights not only help us resolve an enduring evolutionary puzzle, but also offer a unified framework linking genome organization, cellular specialization, and even potential mechanisms underlying carcinogenesis.

genomics↗