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Sapoval, N.

Publications and source records attributed to Sapoval, N..

13 recordsLinked to original sources

DIMPLE: A Tree-Guided Divide-and-Conquer Framework for ILS-Aware Phylogenetic Network Inference on Large-Scale Data

Inferring evolutionary histories of species provides a foundation for comparative genomics and evolutionary analyses. Extensive evidence of reticulate evolution motivates the inference of phylogenetic networks, which represent relationships that species trees cannot capture. However, accurate reconstruction of large phylogenetic networks remains a major challenge because of the vast space of possible network topologies. Here, we propose DIMPLE, a divide-and-conquer framework for phylogenetic network inference without an explicit restriction on network level. DIMPLE uses a tree-of-blobs (TOB), which represents the tree-like relationships between regions of potential reticulation while leaving relationships within those regions unresolved. Within each unresolved region, DIMPLE partitions the set of taxa into pairwise-disjoint subsets, each containing at most a user-specified number of taxa. Multiple division runs are allowed, and subsets from different runs may overlap. DIMPLE infers a subnetwork on each subset, merges the subnetworks within each region, and uses the TOB to assemble the resulting networks into a network on the full taxon set. Experiments with true inputs demonstrate accurate merging, with improved reticulation recovery over existing methods on higher-level networks. With estimated inputs, DIMPLE achieves competitive topological accuracy and more consistently recovers hybrid ancestry than competing methods across varying levels of network complexity. Its computational requirements support analyses of hundreds of taxa. Applications to fern and gymnosperm datasets recover documented hybridization and previously reported phylogenetic conflict.

bioinformatics↗

Kente: A Graph-based Pangenomic Approach for Horizontal Gene Transfer Detection in Microbiomes

MotivationHorizontal gene transfer (HGT) shapes bacterial evolution and microbial ecosystems, yet detecting HGT within microbiomes remains a challenge due to fragmented metagenomic assemblies, reference bias, reliance on gene boundaries, and limited ability to model structural mosaicism and patterns across genomes. MethodsWe present Kente, a novel pangenome graph-based framework designed for HGT detection that aligns metagenomic assembly contigs to a curated database of >600 genus-level bacterial pangenome graphs constructed using minigraph. Kente infers local taxonomic composition along contigs using alignment evidence and classifies candidate transfers using structured clade-transition topologies (e.g., A-B-A sandwich, open tips, and mosaic patterns). A complementary intra-genus module detects inter-species transfers within a single genus graph using segment-level clade annotations. ResultsAcross simulated intra- and inter-genus transfer scenarios, Kente achieves higher precision and comparable recall relative to existing gene-centric microbiome HGT detection approaches while reducing false positives from fragmented assemblies. Application to real human gut metagenomes (HMP2, n = 26) demonstrates Kentes ability to detect candidate cross-lineage transfer regions in complex microbial communities. Runtime profiling shows near-linear scaling with input size, enabling efficient analysis of large metagenomic assemblies. Availability and Implementationhttps://github.com/treangenlab/Kente

bioinformatics↗

Leveraging spectrum of graph sheaf Laplacian as a genome-architecture-aware measure of microbiome diversity

MotivationMeasures of microbial diversity that can be derived directly from metagenomic sequencing data offer a valuable summary view of the underlying complex systems. Prior work has shown that both taxonomic composition and abundances that are captured by standard diversity measures (e.g., Shannon entropy), and structural variation within the metagenome due to gene duplications, losses and horizontal transfers (HGT), can correlate with the hosts health. However, there are no diversity measures available that simultaneously account for the genome architecture and taxonomic composition within the sample. Thus, in this work we propose the spectral energy of a graph sheaf Laplacian as such a measure, and justify its applicability through a simulation study and analysis of biological data. ResultsFirst, we describe a theoretical framework that allows us to combine the features of genome graphs with the taxonomic data. Then, we explore the sensitivity of the proposed diversity measure to genome rearrangements and HGT events in a simulation study. Finally, we explore applicability of our proposed measure to characterization of diversity of human gut metagenomes. We find our proposed measure to offer better discrimination between healthy controls and inflammatory bowel disease (IBD) patients samples (n = 403) in the cohorts analyzed. Availability and Implementationhttps://github.com/nsapoval/bd-gsl

bioinformatics↗

On the consistency of duplication, loss, and deep coalescence gene tree parsimony costs under the multispecies coalescent

Gene tree parsimony (GTP) is a common approach for efficient reconciliation of multiple discordant gene tree phylogenies for the inference of a single species tree. However, despite the popularity of GTP methods due to their low computational costs, prior work has shown that some commonly employed parsimony costs are statistically inconsistent under the multispecies coalescent process. Furthermore, a fine-grained analysis of the inconsistency has indicated potentially complementary behavior of duplication and deep coalescence costs for symmetric and asymmetric species trees. In this work, we prove inconsistency of GTP estimators for all linear combinations of duplication, loss, and deep coalescence scores. We also explore empirical implications of this result by evaluating inference results of several GTP cost schemes under varying levels of incomplete lineage sorting.

bioinformatics↗

GRNITE: Gene Regulatory Network Inference with Text Embeddings

Gene regulatory networks (GRNs) capture complex regulatory relationships that govern gene expression in cells. Inference of GRNs from single-cell RNA-seq (scRNA-seq) data has been an active topic of research in the past several years. However, despite the improvements in the data quality, the GRN inference problem remains a challenging task with many approaches showing variable performance dependent on the organism and cell type. To improve the quality of GRN inference and enable more comprehensive exploratory analyses of GRNs across various phenotypes of interest, we developed a two-stage meta-method called GRNITE. In the first step, GRNITE leverages LLM-based embeddings of plain text gene descriptions to create a prior gene interaction graph, which is then optimized with a graph neural network (GNN) to achieve a "universal" biological prior for GRN inference. In the second step, GRNITE uses a GNN to incorporate information from a GRN inferred from scRNA-seq data with any baseline inference method into our prior. The result of this two-step approach is a near-universal improvement in AUROC and recall of all evaluated methods, with minor trade-offs in precision. Furthermore, GRNITE is a lightweight meta-method, which adds a minimal amount of extra compute time on top of the original GRN inference performed. GRNITE and our pre-trained universal prior GRN are available on GitHub: https://github.com/aliaaz99/GRNITE.

bioinformatics↗

Impact of Data Error on Phylogenetic Network Inference from Gene Trees Under the Multispecies Network Coalescent

Phylogenetic network inference has become an essential tool in evolutionary biology, offering a framework to model complex evolutionary events such as hybridization and horizontal gene transfer. However, a critical but often overlooked challenge is the presence of error in empirical datasets, including sequencing errors, misalignments, and inaccuracies in gene tree estimation. This issue is particularly pressing in the context of phylogenetic networks, which can contain an arbitrary number of parameters and are thus highly susceptible to overfitting. Errors in the input data can lead to artificially inflated network complexity, misrepresenting evolutionary history with non-biological reticulations. In this study,we systematically examine how different sources of data error influence network inference and show that many widely used methods are vulnerable to these distortions. We find that inaccuracies in gene tree estimation and sequence alignment degrade the reliability of inferred networks. These issues are exacerbated when the number of reticulations that an algorithm can infer exceeds the true number of reticulations in the phylogenetic network. Our analysis underscores the importance of accounting for data error when applying network inference methods and provides practical recommendations for minimizing its impact. By highlighting the vulnerabilities of different approaches and demonstrating how errors propagate through the inference process, we offer practical recommendations for optimizing data processing pipelines. Our findings emphasize the necessity of integrating realistic error models into species network inference methods to enhance their reliability and applicability to real-world biological datasets.

bioinformatics↗

Intratumor Heterogeneity Through the Lens of Gene Regulatory Networks

Intratumor heterogeneity (ITH), the presence of heterogeneous genomic and transcriptomic populations in tumor and its implications for the cancer therapies has been one of the focal points of computational cancer biology in the past years. While ITH is well characterized at the genomic level, the regulatory wiring connecting clonal genotypes to transcriptional states remains largely unmapped. To understand whether the evidence for ITH at the gene regulatory level can be inferred from scRNA-seq data, we analyzed scRNA-seq datasets spanning triple-negative breast cancer, colorectal cancer, glioblastoma, and a longitudinal stage IV breast cancer cohort, inferring clone-specific gene regulatory networks (GRNs) and developing quantitative tools to compare them: a Wasserstein distance-based measure of regulatory divergence, a kth order neighborhood similarity framework distinguishing structural from functional rewiring, bootstrap-based edge confidence, and an integrated regulon classification pipeline. Our analyses demonstrate that tumor clones exhibit reproducibly distinct network architectures, and dominant clones show significantly greater regulatory divergence from normal cells than smaller clones, linking regulatory rewiring to clonal fitness. Treatment-induced remodeling exceeds clonal variation, with rewiring exhibiting structural divergence but functional convergence. Regulon analysis further resolved clone-variable, sample-specific, and broadly conserved programs, some of which containing transcription factors whose target genes independently were associated with patient survival.

bioinformatics↗

Theoretical and Empirical Performance of Pseudo-likelihood-based Bayesian Inference of Species Trees under the Multispecies Coalescent

Likelihood-based inference under the multispecies coalescent provides accurate estimates of species trees. However, maximum likelihood and Bayesian inference are both computationally very demanding. Pseudo-likelihood has been previously proposed as a computationally efficient alternative to full phylogenetic likelihood calculations in the context of maximum likelihood estimation. However, theoretical and practical aspects of pseudo-likelihood in the context of Bayesian inference have not been explored. In this work, we provide strong theoretical guarantees and an empirical evaluation of pseudo-likelihood-based Bayesian inference of species trees under the multispecies coalescent. Our contributions are threefold. First, we prove a bound on the convergence rate for species tree topology inference and a Bernstein-von Mises result for branch lengths under model misspecification. Second, we provide an empirical comparison of full- and pseudo-likelihood-based Bayesian inference on synthetic data. Finally, we demonstrate the practical scalability of pseudo-likelihood-based inference by analyzing two biological datasets.

bioinformatics↗

Lightweight taxonomic profiling of long-read sequenced metagenomes with Lemur and Magnet

The advent of long-read sequencing of microbiomes necessitates the development of new taxonomic profilers tailored to long-read shotgun metagenomic datasets. Here, we introduce Lemur and Magnet, a pair of tools optimized for lightweight and accurate taxonomic profiling for long-read shotgun metagenomic datasets. Lemur is a marker-gene-based method that leverages an EM algorithm to reduce false positive calls while preserving true positives; Magnet is a whole-genome read-mapping-based method that provides detailed presence and absence calls for bacterial genomes. We demonstrate that Lemur and Magnet can run in minutes to hours on a laptop with 32 GB of RAM, even for large inputs, a crucial feature given the portability of long-read sequencing machines. Furthermore, the marker gene database used by Lemur is only 4 GB and contains information from over 300,000 RefSeq genomes. Lemur and Magnet are open-source and available at https://github.com/treangenlab/lemur and https://github.com/treangenlab/magnet.

bioinformatics↗

Olivar: fully automated and variant aware primer design for multiplex tiled amplicon sequencing of pathogen genomes

Tiled amplicon sequencing has served as an essential tool for tracking the spread and evolution of pathogens. Over 2 million complete SARS-CoV-2 genomes are now publicly available, most sequenced and assembled via tiled amplicon sequencing. While computational tools for tiled amplicon design exist, they require downstream manual optimization both computationally and experimentally, which is slow and costly. Here we present Olivar, a first step towards a fully automated, variant-aware design of tiled amplicons for pathogen genomes. Olivar converts each nucleotide of the target genome into a numeric risk score, capturing undesired sequence features that should be avoided. In a direct comparison with PrimalScheme, we show that Olivar has fewer SNPs overlapping with primers and predicted PCR byproducts. We also compared Olivar head-to-head with ARTIC v4.1, the most widely used primer set for SARS-CoV-2 sequencing, and show Olivar yields similar read mapping rates ([~]90%) and better coverage to the manually designed ARTIC v4.1 amplicons. We also evaluated Olivar on real wastewater samples and found that Olivar had up to 3-fold higher mapping rates while retaining similar coverage. In summary, Olivar automates and accelerates the generation of tiled amplicons, even in situations of high mutation frequency and/or density. Olivar is available as a web application at https://olivar.rice.edu. Olivar can also be installed locally as a command line tool with Bioconda. Source code, installation guide and usage are available at https://github.com/treangenlab/Olivar.

bioinformatics↗

The Great Deceiver: miR-2392's Hidden Role in Driving SARS-CoV-2 Infection

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

systems biology↗

Hidden genomic diversity of SARS-CoV-2: implications for qRT-PCR diagnostics and transmission

The COVID-19 pandemic has sparked an urgent need to uncover the underlying biology of this devastating disease. Though RNA viruses mutate more rapidly than DNA viruses, there are a relatively small number of single nucleotide polymorphisms (SNPs) that differentiate the main SARS-CoV-2 clades that have spread throughout the world. In this study, we investigated over 7,000 SARS-CoV-2 datasets to unveil both intrahost and interhost diversity. Our intrahost and interhost diversity analyses yielded three major observations. First, the mutational profile of SARS-CoV-2 highlights iSNV and SNP similarity, albeit with high variability in C>T changes. Second, iSNV and SNP patterns in SARS-CoV-2 are more similar to MERS-CoV than SARS-CoV-1. Third, a significant fraction of small indels fuel the genetic diversity of SARS-CoV-2. Altogether, our findings provide insight into SARS-CoV-2 genomic diversity, inform the design of detection tests, and highlight the potential of iSNVs for tracking the transmission of SARS-CoV-2.

genomics↗

KOMB: Taxonomy-oblivious Characterization of Metagenome Dynamics via K-core Decomposition

Characterizing metagenomic samples via kmer-based, database-dependent taxonomic classification methods has provided crucial insight into underlying host-associated microbiome dynamics. However, novel approaches are needed that are able to track microbial community dynamics within metagenomes to elucidate genome flux in response to perturbations and disease states. Here we describe KOMB, a novel approach for tracking homologous regions within microbiomes. KOMB utilizes K-core graph decomposition on metagenome assembly graphs to identify repetitive and homologous regions to varying degrees of resolution. K-core performs a hierarchical decomposition which partitions the graph into shells containing nodes having degree at least K, called K-shells, yielding O(V + E) complexity compared to exact betweenness centrality complexity of O(V E) found in prior related approaches. We show through rigorous validation on simulated, synthetic, and real metagenomic datasets that KOMB accurately recovers and profiles repetitive and homologous genomic regions across organisms in the sample. KOMB can also identify functionally-rich regions in Human Microbiome Project (HMP) datasets, and can be used to analyze longitudinal data and identify pivotal taxa in fecal microbiota transplantation (FMT) samples. In summary, KOMB represents a novel approach to microbiome characterization that can efficiently identify sequences of interest in metagenomes.

bioinformatics↗