Biology subjects

Petrov, D. A.

Publications and source records attributed to Petrov, D. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Order invariance of fitness makes evolution predictable despite strong history-dependent effects

Environmental change is ubiquitous in nature, yet understanding its effect on the predictability of evolution remains a challenge. Previous work in microbes has shown that growth and fitness in a particular environment can depend strongly on the environments encountered previously. If such history-dependent effects are large, then any sequence of environments must be thought of as unique, and even a modest number of environments could generate a combinatorially large number of evolutionary paths. This would make evolution in changing environments difficult to predict. Here, we use cycles of three environments, which is the smallest number of environments which allow for comparisons of different environmental orderings -- X [->] Y [->] Z [->] X vs X [->] Z [->] Y [->] X -- to empirically test how environmental order affects the fitness of S. cerevisiae mutants. We measured the fitness of ~900 adaptive mutants in distinct three-environment cycles, and find large history-dependent effects which cause fitness in individual environmental components to differ drastically across the two directions of the cycle. However, these effects tend to compensate for each other, resulting in similar overall fitness across the whole cycle. This is true even when we specifically conduct experimental evolution in both directions of the same three-environment cycle. Of the ~450 mutants we isolated, only a small number of strains showed higher fitness in the direction in which they evolved. By splitting the contribution of each environment on fitness into its effect on the current and next component, we show that the invariance of overall fitness to environment order emerges because the effect of an environment on the next component is largely independent of the identity of the subsequent component, and can be captured by an additive model. Despite this general pattern of compensation, we do find instances of non-additivity, some of which are partly due to history-dependent effects lasting beyond two growth components. Overall, these results suggest that despite large history-dependent effects, fitness across a sequence of environments can be surprisingly predictable.

evolutionary biology↗

bioRxiv2026

Transcriptional Response to Tumor Mutational Burden Is Consistent Across Cancer Types

Tumor mutational burden (TMB) shapes tumor transcriptional state, but studies typically describe this response as an average effect pooled across cancer types. Whether that average reflects a consistent response present within individual cancer types, or is an artifact of merging heterogeneous, tissue-specific responses, remains unresolved. Here we analyze ~9,100 tumors across 32 TCGA cancer types to test whether the transcriptional response to TMB is genuinely consistent across tissues. We construct a TMB axis score from TMB-associated genes upregulated with increasing TMB, yielding a sample-level measure of response strength, and subsequently decompose it at the component and pathway/complex levels. The pooled transcriptional response to TMB stays largely consistent within each cancer type, and no single cancer is driving the pooled signal. This consistency was also observed at the component and pathway/complex levels. These findings support TMB as a promising tissue-agnostic signature, with implications for tissue-agnostic therapeutic targeting.

cancer biology↗

bioRxiv2026

Persistent, Multi-Species Outbreaks and Long-Range Transmissions of a Measles-Like Virus

Canine distemper--a measles-like disease with high mortality and presently without a cure--poses a major threat to wild and domestic carnivores globally. Domestic dogs are generally considered to be the main reservoir and long-range transmitter of the disease, but the role of wildlife is likely underestimated and the long-term persistence of CDV in wildlife has never been assessed. We sequenced canine distemper virus (CDV) full and partial genomes that were sampled over a decade (2012-2021) from Arctic foxes and other canids in Alaska and Yellowstone, and compiled a dataset of all published CDV genomes sampled across 32 species globally. We show the first ever evidence of persistence of CDV in wildlife (for almost a decade) with explosive transmission dynamics crossing host species barriers. Strains sampled from the Arctic for the first time connect North America to Eurasia, and are distinct from the Yellowstone strain and other known North American lineages. This suggests that separate wildlife outbreaks occur concurrently in North America, with possible introductions from Eurasia. The long-term persistence, long-range movement and explosive spread of this devastating panzootic virus that we document within wildlife is alarming and highlights the need for increased monitoring efforts to better protect wildlife populations globally.

genomics↗

bioRxiv2025

Assessing nonlinearities in the GFP random mutagenesis landscape using the Power Transform

Epistasis, a non-additive contribution of mutations to fitness, complicates genotype-to-phenotype prediction and is often confounded by nonlinearities in phenotype measurements. The Power Transform method, particularly Box-Cox, has been used to reduce epistasis in small, combinatorially complete datasets by linearizing phenotypic scales. However, its applicability to large landscapes, especially those generated by (quasi-)random mutagenesis, remains unclear. Here, we apply both Box-Cox and Yeo-Johnson Power Transforms to the extensively characterized green fluorescent protein (GFP) fitness landscape, which contains hundreds of thousands of two- and three-dimensional combinatorially complete datasets. Surprisingly, when applied to individual hypercubes, Box-Cox reduces pairwise epistasis by 19.4% on average, whereas Yeo-Johnson - despite accommodating negative values - slightly increases epistasis (by 4.45%). Moreover, in a notable fraction of hypercubes, both methods increase the magnitude of epistatic coefficients, indicating that Power Transform does not universally reduce nonlinearity at the local scale. In contrast, applying Yeo-Johnson to the largest connected component of the GFP landscape (20,872 genotypes) successfully reduces both pairwise (by 3.86%) and third-order epistasis (by 11.6%), with the majority of coefficients decreasing in magnitude. These results demonstrate that Power Transform can be extended to large, real-world landscapes generated by random mutagenesis, but only when applied to connected sublandscapes. Our findings highlight a critical distinction between global and local linearization and caution against assuming that Power Transform always diminishes epistasis.

bioinformatics↗

bioRxiv2025

Community coalescence reveals strong selection and coexistence within species in complex microbial communities

Complex microbial ecosystems harbor extensive intra-species diversity, but the fitness consequences of this genetic variation are poorly understood in community settings. Here we address this question by competing in vitro gut communities derived from different human donors, revealing the emergent fitness differences between conspecific strains as they competed within larger communities. Most pairs of strains experienced strong and context-dependent selection, even when their parent communities were originally selected in the same nutrient environment. However, these fitness differences typically attenuated over time due to biotic interactions within the community, leading to extended coexistence within many species, and competitive exclusion in others. These results support the view that conspecific strains can fulfill distinct ecological roles when competing within a diverse community, even when their genomic diversity exhibits the hallmarks of a single biological species.

evolutionary biology↗

bioRxiv2025

High-resolution mapping of a rapidly evolving complex trait reveals genotype-phenotype stability and an unpredictable genetic architecture of adaptation

The extent to which adaptation can be predicted is unknown. Here, we leveraged a longitudinal sampling design to test the efficacy of genomic prediction of trait evolution in an ecologically-relevant setting. Specifically, we monitored genome-wide allele frequencies and pigmentation variation in genetically diverse populations of Drosophila melanogaster across seven generations of evolution in both field mesocosms and a controlled, lab-based setting. At two points during trait evolution, we conducted a high-powered quantification of trait architecture that produced a well-resolved genotype-phenotype map. While we were able to use this map to correctly infer the direction of pigmentation evolution in both the field and lab mesocosms, the particular loci responding to selection, and thus the architecture of adaptation itself, was largely unpredictable. Further, we quantified a striking stability of the genotype-phenotype map, even across independent and genetically diverged populations. Our results hold implications for both the promise and limitations of genomic prediction.

evolutionary biology↗

bioRxiv2025

Learning the Shape of Evolutionary Landscapes: Geometric Deep Learning Reveals Hidden Structure in Phenotype-to-Fitness Maps

Elucidating the complex relationships between genotypes, phenotypes, and fitness remains one of the fundamental challenges in evolutionary biology. Part of the difficulty arises from the enormous number of possible genotypes and the lack of understanding of the underlying phenotypic differences driving adaptation. Here, we present a computational method that takes advantage of modern high-throughput fitness measurements to learn a map from high-dimensional fitness profiles to a low-dimensional latent space in a geometry-informed manner. We demonstrate that our approach using a Riemannian Hamiltonian Variational Autoencoder (RHVAE) outperforms traditional linear dimensionality reduction techniques by capturing the nonlinear structure of the phenotype-fitness map. When applied to simulated adaptive dynamics, we show that the learned latent space retains information about the underlying adaptive phenotypic space and accurately reconstructs complex fitness landscapes. We then apply this method to a dataset of high-throughput fitness measurements of E. coli under different antibiotic pressures and demonstrate superior predictive power for out-of-sample data compared to linear approaches. Our work provides a data-driven implementation of Fishers geometric model of adaptation, transforming it from a theoretical framework into an empirically grounded approach for understanding evolutionary dynamics using modern deep learning methods.

evolutionary biology↗

bioRxiv2025

Manual validation finds only ultra-long long-read sequencing enables faithful, population-level structural variant calling in Drosophila melanogaster euchromatin

The increasing accessibility of long-read sequencing and the rapid development of automated variant callers are promoting the generation of population-level structural variation data. However, the effect of the length of long-reads on automated variant callers is not well understood, especially for non-human species. Here we show that only ultra-long long-reads, with read N50s greater than 50kb, are capable of accurately calling structural variants of any size in Drosophila melanogaster euchromatin. We used Oxford Nanopore Technologies to long-read sequence eight, inbred D. melanogaster strains to extremely high coverage (mean 238x), and we then downsampled the reads to create read pools of different length distributions. We assembled genomes from these different read-length pools and used both read-based and assembly-based structural variant callers to call variants in each strain before merging the calls into population-level datasets. We manually validated over 2,300 putative structural variants to assess the accuracy of the variant calls across the different read-length distributions and to determine the cause and rates of false positive errors. We found that more than half of all structural-variant-calling errors stem from misaligned reads that contain mobile elements or are located in repetitive and complex regions. Overall, our results show that long reads need to be at least three times longer than the repetitive and mobile elements found in the genome in order to accurately call structural variants at the population level.

genomics↗

bioRxiv2025

Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer

The impact of cancer driving mutations in regulating immunosurveillance throughout tumor development remains poorly understood. To better understand the contribution of tumor genotype to immunosurveillance, we generated and validated lentiviral vectors that create an epi-allelic series of increasingly immunogenic neoantigens. This vector system is compatible with autochthonous Cre-regulated cancer models, CRISPR/Cas9-mediated somatic genome editing, and tumor barcoding. Here, we show that in the context of KRAS-driven lung cancer and strong neoantigen expression, tumor suppressor genotype dictates the degree of immune cell recruitment, positive selection of tumors with neoantigen silencing, and tumor outgrowth. By quantifying the impact of 11 commonly inactivated tumor suppressor genes on tumor growth across neoantigenic contexts, we show that the growth promoting effects of tumor suppressor gene inactivation correlate with increasing sensitivity to immunosurveillance. Importantly, specific genotypes dramatically increase or decrease sensitivity to immunosurveillance independently of their growth promoting effects. We propose a model of immunoediting in which tumor suppressor gene inactivation works in tandem with neoantigen expression to shape tumor immunosurveillance and immunoediting such that the same neoantigens uniquely modulate tumor immunoediting depending on the genetic context. One Sentence SummaryHere we uncover an under-appreciated role for tumor suppressor gene inactivation in shaping immunoediting upon neoantigen expression.

cancer biology↗

bioRxiv2024

Massively parallel experimental interrogation of natural variants in ancient signaling pathways reveals both purifying selection and local adaptation

The nature of standing genetic variation remains a central debate in population genetics, with differing perspectives on whether common variants are almost always neutral as suggested by neutral and nearly neutral theories or whether they can commonly have large functional and fitness effects as proposed by the balance theory. We address this question by mapping the fitness effects of over 9,000 natural variants in the Ras/PKA and TOR/Sch9 pathways--key regulators of cell proliferation in eukaryotes--across four conditions in Saccharomyces cerevisiae. While most variants are neutral in our assay, [~]3,500 exhibited significant fitness effects. These non-neutral variants tend to be missense and to affect conserved, more densely packed, and less solvent-exposed protein regions. While some of these non-neutral variants are younger and rarer, and more often found in heterozygous states--consistent with purifying selection--a substantial fraction is present at high frequencies in the population, which is expected under balancing selection. Indeed, we find that variants with a positive fitness effect in our laboratory measurement show strong signs of local adaptation as they tend to be found specifically in domesticated strains isolated from human-made environments. Our findings support the view that while many common variants might be effectively neutral, a significant proportion have locally adaptive functional consequences and are driven into a subset of the population by local positive selection. This study highlights the potential to combine high-throughput precision genome editing with fitness measurements to explore natural genetic variation on a pathway-wide scale, thereby bridging the gap between population genetics and functional genomics to understand the nature of evolutionary forces in the wild.

evolutionary biology↗

bioRxiv2024

Dominance reversal protects large-effect resistance polymorphisms in temporally varying environments

Large-effect functional genetic variation is commonly found in natural populations, even though natural selection should erode such variants. Theory suggests that under fluctuating selective pressures, beneficial reversal of dominance - where alleles are dominant when beneficial and recessive when deleterious - can protect these loci from selection, allowing them to persist. However, empirical evidence for this mechanism remains elusive because testing requires direct measurements of selection and dominance in natural conditions. Here, we show that insecticide-resistant alleles at the Ace locus in Drosophila melanogaster persist worldwide at intermediate frequencies and exhibit beneficial reversal of dominance. By combining laboratory and large-scale field mesocosm experiments with insecticide manipulation, and mathematical modeling, we show that the benefits of the resistant Ace alleles are dominant while their fitness costs recessive. We further show that fluctuating insecticide selection generates chromosome-scale genomic perturbations at sites linked to the resistant Ace alleles, revealing broader genomic consequences of this mechanism. Overall, our results suggest that beneficial reversal of dominance contributes to the maintenance of functional genetic variation and impacts patterns of genomic diversity via linked fluctuating selection.

evolutionary biology↗

bioRxiv2024

Next-generation snow leopard population assessment tool: multiplex-PCR SNP panel for individual identification from feces

Snow leopards, Panthera uncia, are under threat from numerous pressures and are the focus of a great deal of conservation efforts. However, their elusive nature makes it difficult to estimate population sizes. Current methods used to monitor local population sizes include visually identifying individuals from camera trap photos and genetically identifying individuals from fecal samples using microsatellite loci. Here, we present a new method for identifying snow leopard individuals from fecal samples using a multiplex PCR single nucleotide polymorphism (SNP) panel method. The SNP panel we present consists of 144 SNPs and utilizes next-generation sequencing technology, making it cheaper and easier than current microsatellite methods. We validate our SNP panel with paired tissue and fecal samples from zoo individuals, showing a minimum of 96.7% accuracy in allele calls per run. We then generate SNP data from 235 field-collected fecal samples from across Pakistan to show that the panel can reliably identify individuals from low-quality fecal samples of unknown age and is robust to contamination. We also show that our SNP panel has the capability to identify first-order relatives and provides insights into the geographic origin of samples. This SNP panel will empower the snow leopard research community in their efforts to assess local and global snow leopard population sizes. More broadly, we present a method for developing a SNP panel that utilizes open source software for SNP selection and primer design, Illumina sequencing technology, and a streamlined lab and bioinformatics protocol which can be used to create similar SNP panels for any species of interest for which adequate genomic reference data is available.

genetics↗

bioRxiv2024

A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and show that STAG2 is uniquely tumor suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility and 3D genome conformation that impact cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relates STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin mediated mechanisms of lung tumor suppression. SUMMARYSTAG2 is a frequently mutated cohesin subunit across several cancers and one of the most important functional suppressors of lung adenocarcinoma. Our findings underscore important roles of STAG2 in suppressing lung tumorigenesis and highlight a STAG2-PAXIP1/PAGR1 tumor-suppressive program that may transcend cancer type.

cancer biology↗

bioRxiv2024

Drosophila melanogaster pigmentation demonstrates adaptive phenotypic parallelism but genomic unpredictability over multiple timescales

Populations are capable of responding to environmental change over ecological timescales via adaptive tracking. However, the translation from patterns of allele frequency change to rapid adaptation of complex traits remains unresolved. We used abdominal pigmentation in Drosophila melanogaster as a model phenotype to address the nature, genetic architecture, and repeatability of rapid adaptation in the field. We show that D. melanogaster pigmentation evolves as a highly parallel and deterministic response to shared environmental gradients across latitude and season in natural North American populations. We then experimentally evolved replicate, genetically diverse fly populations in field mesocosms to remove any confounding effects of demography and/or cryptic structure that may drive patterns in wild populations; we show that pigmentation rapidly responds, in parallel, in fewer than fifteen generations. Thus, pigmentation evolves concordantly in response to spatial and temporal climatic gradients. We next examined whether phenotypic differentiation was associated with allele frequency change at loci with established links to genetic variance in pigmentation in natural populations. We found that across all spatial and temporal scales, phenotypic patterns were associated with variation at pigmentation-related loci, and the sets of genes we identified in each context were largely nonoverlapping. Therefore, our findings suggest that parallel phenotypic evolution is associated with distinct components of the polygenic architecture shifting across each environmental gradient to produce redundant adaptive patterns.

evolutionary biology↗

bioRxiv2024

Aging represses lung tumorigenesis and alters tumor suppression

Most cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation -- widely understood to contribute to cancer risk -- it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.

cancer biology↗

bioRxiv2024

Parameterizing Pantherinae: de novo mutation rate estimates from Panthera and Neofelis pedigrees

Estimates of de novo mutation rates are essential for phylogenetic and demographic analyses, but their inference has previously been impeded by high error rates in sequence data and uncertainty in the fossil record. Here, we directly estimate de novo germline mutation rates for all extant members of Panthera, as well as the closely related outgroup Neofelis nebulosa, using pedigrees. We use a previously validated pipeline (RatesTools) to calculate mutation rate for each species and subsequently explore the impacts of the novel rates on historic effective population size estimates in each of these charismatic felids of conservation concern. Importantly, we find that the choice of reference genome, the data type and coverage, and the individual all impact estimates of the mutation rate. Despite these stochastic effects, we inferred that base pair mutation rates for all species fell between 0.5 and 1.4e-08 per generation per base pair (mean 0.81e-08 {+/-} 0.35-08 across Pantherinae). Our results provide a cautionary view on inter-species mutation rate comparisons, given the error associated with the reference genome choice and sequencing depth of coverage of the individuals.

evolutionary biology↗

bioRxiv2024

Combinatorial in vivo genome editing identifies widespread epistasis during lung tumorigenesis

Lung adenocarcinoma, the most common subtype of lung cancer, is genomically complex, with tumors containing tens to hundreds of non-synonymous mutations. However, little is understood about how genes interact with each other to enable tumorigenesis in vivo, largely due to a lack of methods for investigating genetic interactions in a high-throughput and multiplexed manner. Here, we employed a novel platform to generate tumors with all pairwise inactivation of ten tumor suppressor genes within an autochthonous mouse model of oncogenic KRAS-driven lung cancer. By quantifying the fitness of tumors with every single and double mutant genotype, we show that most tumor suppressor genetic interactions exhibited negative epistasis, with diminishing returns on tumor fitness. In contrast, Apc inactivation showed positive epistasis with the inactivation of several other genes, including dramatically synergistic effects on tumor fitness in combination with Lkb1 or Nf1 inactivation. This approach has the potential to expand the scope of genetic interactions that may be functionally characterized in vivo, which could lead to a better understanding of how complex tumor genotypes impact each step of carcinogenesis.

cancer biology↗

bioRxiv2023

Competition for shared resources increases the impact of propagule size during coalescence of gut microbial communities

The long-term success of introduced populations depends on their initial size and ability to compete against existing residents, but it remains unclear how these factors collectively shape colonization. Here, we investigate how initial population (propagule) size and resource competition interact during community coalescence by systematically mixing eight pairs of in vitro microbial communities at ratios that vary over six orders of magnitude, and we compare our results to a neutral ecological model. Although the composition of the resulting co-cultures deviated substantially from neutral expectations, each co-culture contained species whose relative abundance depended on propagule size even after [~]40 generations of growth. Using a consumer-resource model, we show that this dose-dependent colonization can arise when resident and introduced species have high niche overlap and consume shared resources at similar rates. This model predicts that propagule size will have larger, longer-lasting effects in diverse communities in which niche overlap is higher, and we experimentally confirm that strain isolates show stronger dose dependence when introduced into diverse communities than in pairwise co-culture. This work shows how neutral-like colonization dynamics can emerge from non-neutral resource competition and have lasting effects on the outcomes of community coalescence.

ecology↗