bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.03.16.532885

Standardizing and applying a mating-based whole-genome simulation approach reveals caution in using chromosome-level PCA and kinship estimates

Cui, Z.·Schumacher, F.
View original source ↗Export metadata ↓

Abstract

This paper presents a new and efficient method for simulating pseudo-genotype data using the standardized protocol of SLiM, which offers a flexible alternative to traditional methods that rely on large genetic datasets. These datasets can be time-consuming to obtain, especially when institutional review board (IRB) review is involved, making simulation an attractive alternative. While HapGen v2 is the most popular genotype simulator, we found that SLiM has the potential for more customizable simulation to meet multiple needs. To validate our new method, we compared its performance among parallel simulations varying multiple parameters. Our results showed that SLiM is capable of simulating samples up to 333 times the input size, with a low rate of simulated samples that are 2nd or closer relatives (REV), making it a promising alternative to HapGen. We also applied our whole-genome simulation approach to sensitivity analyses of chromosome-level principal component analysis (PCA) and kinship estimation. Our findings revealed important insights into the sensitivity of PCA and kinship estimation, highlighting the unequal distribution of population structure across chromosomes and ancestries. Furthermore, our study provides experimental support for avoiding chromosome-level quality control statistics. Overall, our standardized protocol of SLiM offers a flexible new way to produce pseudo-genotype data, and our findings provide valuable insights that can advance research in the field. By demonstrating the potential of SLiM for more customizable simulations and highlighting the importance of considering the distribution of population structure across chromosomes and ancestries, our research has significant implications for the study of genetics and genomics. Author SummaryIn this publication, we introduce a novel approach to genotype simulation using a mating-based strategy in SLiM. Our approach mimics mitosis computationally and stands out as the only one available as of December 2022 that can maintain cross-chromosome associations during whole-genome level simulation, with no competitors in sight. Additionally, our approach is applicable to regional or chromosomal genotype simulation. When compared to the current gold-standard chromosome-level simulator, HapGen, our approach exhibits superior performance when generating large sample sizes (>13,000). We provide an application example that uses whole-genome simulation to underscore the importance of whole-genome quality control (QC) statistics, such as principal component analysis (PCA) and kinship estimates, compared to the chromosome-level ones. Results of the application indicate instability and bias in the chromosome-level QC statistics. Overall, our approach represents a valuable tool for genetics research that can assist in the evaluation and validation of genetic analyses, and people should avoid chromosome-level QC statistics.

Explore related subjects

bioinformaticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Cui, Z., Schumacher, F.. 2023-03-16. Standardizing and applying a mating-based whole-genome simulation approach reveals caution in using chromosome-level PCA and kinship estimates. https://doi.org/10.1101/2023.03.16.532885

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

KEEP EXPLORING

Related preprints

bioRxiv2026

spatialMET: an open and scalable framework for spatial metabolomics analysis

Mass spectrometry imaging (MSI) enables spatially resolved metabolomics in intact tissue sections, but analysis remains challenging at scale. Existing MSI workflows often require users to combine multiple software tools, while others rely on proprietary vendor software that limits interoperability and reproducibility. To address these challenges, we developed spatialMET, an open-source framework that provides an end-to-end workflow for MSI analysis. spatialMET provides a unified platform for preprocessing, spatial domain detection, and visualization. Downstream analyses include differential abundance testing, spatial autocorrelation and gradient analysis, dimensionality reduction, and correlation network analysis. Spatial domain detection uses hcdist, a C-based hierarchical clustering implementation that substantially reduces runtime and memory use relative to existing R-based approaches. spatialMET can be run through an interactive R Shiny application or as a standalone command-line workflow for larger datasets or high-performance computing environments. Applied to mouse small cell lung cancer MALDI-MSI data containing 284,673 pixels, spatialMET identified tumor-associated, stromal, and adjacent lung spatial domains that aligned with matched histology. Differential abundance analysis identified 117 m/z features that differed between tumor and stromal regions, while spatial autocorrelation analyses revealed spatially structured abundance patterns. Applying spatialMET to mouse lung adenocarcinoma data from an entire lung lobe containing 338,477 pixels further demonstrated scalability and captured spatial heterogeneity across tumor and surrounding lung tissue. In summary, spatialMET provides a scalable, open-source framework for end-to-end spatial metabolomics analysis, and it is distributed as a Docker container for reproducible deployment. Source code and installation instructions are available at https://github.com/biodatalab/spatialMET.

bioinformatics↗
bioRxiv2026

Probing the transcriptome response to shivering in skeletal muscle using a multilayered bioinformatics approach

Cold acclimation holds therapeutic potential for improving metabolic health. We previously demonstrated that repeated cold-induced shivering enhances insulin sensitivity in humans. However, the molecular pathways that underlie the skeletal muscle shivering response, and how these relate to beneficial physiological effects, remain poorly understood. In this study, we combined complementary bioinformatics approaches to allow in-depth analysis of the transcriptomic response of human skeletal muscle to repeated shivering. We identified a robust transcriptional signature and show a sex-specific component in the shivering skeletal muscle response, which seemed to diminish following cold adaptation. Our findings provide mechanistic insights into cold-induced muscle adaptations, shed light on potential interesting molecular targets for further investigation, and emphasize the importance of including both sexes in future cold acclimation studies.

bioinformatics↗
bioRxiv2026

An Information Geometry approach to model topological trajectories and Gene Expression Radius from UMAP geometry.

Understanding the relationship between gene expression dynamics and cellular identity remains a central challenge in single cell biology. Here, we introduce a novel computational and mathematical framework that integrates information geometry, fuzzy topology, and UMAP analysis to model gene expression landscapes derived from single cell RNA sequencing data. We formalize gene expression data as a fuzzy topological space, where interactions between expression points are governed by probabilistic distributions inspired by manifold learning approaches such as UMAP. Within this framework, we define an information geometric structure through a Fisher metric induced by these distributions, enabling the computation of geodesic trajectories that capture cellular differentiation processes. A key contribution of this work is the derivation of analytical conditions, expressed as expression radius formulas, that characterize local neighborhoods in gene expression space. These conditions allow for the identification of genes associated with stem cell states and predictions in transitional cell types in future work. Application of the proposed framework to single cell datasets reveals biologically meaningful gene sets enriched in key regulatory pathways and transcription factors, demonstrating the capacity of our approach to uncover latent structure in complex gene expression data. Our results suggest that integrating differential geometry with statistical learning theory offers a powerful paradigm for modeling genotype and phenotype relationships and cellular state transitions, with potential implications for precision medicine and systems biology.

bioinformatics↗