Search bioRxiv⌕ Search

bioRxiv · 10.1101/2020.07.23.216606

Signal, bias, and the role of transcriptome assembly quality in phylogenomic inference

Abstract

The empirical details of whole transcriptome sequencing and assembly have been thoroughly evaluated, but few studies have addressed how user-defined aspects of the assembly process may influence performance in phylogenomic analyses. Errors in transcriptome assembly could affect ortholog prediction, alignment quality, and phylogenetic signal. Here we investigate the impacts of transcriptome assembly quality in phylogenomic studies by constructing phylogenomic data matrices from alternative transcriptome assemblies representing high-quality and intentionally low-quality assembly outcomes. We leveraged a well-resolved topology for craniates to apply a topological constraint to our analyses, providing a way to quantify phylogenetic signal. Craniates are amply represented in publicly available raw RNA-seq repositories, allowing us to control for transcriptome tissue type as well. By studying the performance of phylogenomic datasets derived from these alternative high- and low-quality inputs in a controlled experiment, we show that high-quality transcriptomes produce richer phylogenomic datasets with partitions that have lower alignment ambiguity, less compositional bias, and stronger phylogenetic signal than low-quality transcriptome assemblies. Our findings demonstrate the importance of transcriptome assembly in phylogenomic analyses and suggest that a portion of the uncertainty observed in phylogenomic studies could be alleviated at the assembly stage.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Spillane, J. L., LaPolice, T. M., MacManes, M. D., Plachetzki, D. C.. 2020-07-24. Signal, bias, and the role of transcriptome assembly quality in phylogenomic inference. https://doi.org/10.1101/2020.07.23.216606

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Large language models complement established workflows for mechanistic model construction and refinement in systems biology

Mechanistic models provide a framework for describing, understanding, and predicting biological processes, but their development requires an interdisciplinary team with expertise in biology, mathematics, and computation. Here we present Octomod, a multi-agent workflow based on large language models (LLMs) that integrates biological knowledge retrieval, model construction, parameter estimation, and hypothesis testing. Built on established software tools, including AMICI and pyPESTO, and community standards, including SBML and PEtab, Octomod supports model development and refinement through natural-language interaction with a user. The agents' proposals must pass defined checks and the user's decision before they are used. Every input, model, check, and decision is recorded, so that model building remains transparent and reproducible. We applied Octomod to four problems. Three used published data and differ in model size and in how much the user guided the run: Octomod constructed a model that matched a published model without user guidance, supported the interactive refinement of a gene-regulatory model, and built models of cell-cell communication that explained the responses of five immune cell types to different stimuli. In the fourth application, on newly generated and unpublished lipidomics data, Octomod helped to determine which processes the measurements could inform, identify unresolved label fluxes, and reduce a supplied model to those processes. Together, these results show how LLMs can strengthen and complement established workflows for constructing and refining biologically informed models.

systems biology↗

A Mathematical Model Connecting Appetite-Driven Food Intake to Metabolic Changes across Diet and GLP-1RA Treatments in Mice

Mouse models are widely used to study obesity and the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on appetite-driven meal responses and eating behaviours. However, connecting these behavioural changes to disease prevention remains limited. One reason is that eating behaviour is often summarised as daily or weekly energy intake, obscuring meal-level dynamics. Here we present a mathematical model of mouse appetite-driven food intake across diets and treatment with the GLP-1RAs semaglutide and exenatide. The model jointly described three studies and passed both qualitative assessments and a statistical {chi}2 test (disagreement<threshold, 348<1111). Predictive performance was subsequently validated using four pre-existing studies and one new study. Finally, the model was used to simulate mouse populations under dietary and GLP-1RA interventions, with predictions showing qualitative agreement with the literature. This work aids preclinical drug discovery, supports mouse study design, and improves understanding of how individual meals accumulate into long-term physiological changes.

systems biology↗

Generalized inference of noise-corrected state variability in single cells

Single-cell omics methods operate at their detection limit and are less conducive to technical controls than mini-bulk approaches, which combine cells of the same type before profiling. To integrate mini-bulk samples with paired split-pool controls more holistically, we built stochprofIC, an algorithm that considers data, noise, and covariates in a distributional-regression framework. We vet stochprofIC with synthetic datasets and compare against an adjusted-variance alternative using mini-bulk data in mouse brains and human breast cancers. The noise-batch corrections provided by stochprofIC enable inference of the single-cell populations comprising the mini-bulk, which are validated repeatedly by RNA FISH in different contexts. We use stochprofIC outputs as input to a systems model of nucleocytoplasmic transport and distinguish heterogeneous trafficking states. Pharmacologic inhibition of a MAP3K11-high state inhibits apoptosis in primary breast-cancer organoids, supporting relevance to phenotypes. By deconvolving changes in location and scale, stochprofIC supports mini-bulking when high-sensitivity and reliability profiles are important.

systems biology↗