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Biology subjects

Swarna, N. P.

Publications and source records attributed to Swarna, N. P..

3 recordsLinked to original sources

Dimensionality Reduction for Cyclic Compositional Data

The cyclic nature of many biological systems is frequently reflected in periodic gene expression patterns. Standard dimensionality reductions can reveal such variation but do not link a sample's position on a cycle to an ordering of the molecular features that define it. We introduce clrcycle, which applies a centered log-ratio transformation, learns a cyclic feature ordering by maximizing variance captured by the first Fourier mode, and projects samples onto the corresponding cosine and sine coordinates. The resulting two-dimensional geometry assigns each sample a phase and a radius measuring the magnitude of its projection onto the learned Fourier circle. Across a mouse circadian atlas, clrcycle recovers known temporal organization and reveals tissue-specific differences in rhythmic timing. In FUCCI-profiled single cells, clrcycle represents independently measured cell-cycle phase in two-dimensional coordinates more reliably than conventional two-dimensional embeddings. In human endometrium, a circular coordinate learned from 250 highly variable genes recovers menstrual-stage organization and can stage unseen endometrial biopsies. Together, these results establish clrcycle as powerful, explicitly circular dimensionality reduction technique to quantify high-dimensional cyclic variation across biological cycles.

bioinformatics↗

Determining gene specificity from multivariate single-cell RNA sequencing data

An important application of single-cell genomics experiments is to identify genes specific to biological categories or experimental conditions. Although numerous approaches have been proposed to identify such genes, we consider an axiomatic approach based on defining properties that a specificity measure should have. This leads us to develop ember (Entropy Metrics for Biological ExploRation), which we show is the only method satisfying four key desired properties for a specificity measure. Applying ember to eight tissues from eight founder mouse strains, we find that gene specificity is often unintuitive: canonical markers can be supplanted, housekeeping genes are context-dependent, and mouse strain can drive unexpected cell type switching. Unsupervised learning on entropy metrics uncovers shared genes specialized to male gonads and kidney, as well as genes specific to non-consecutive developmental stages in the kidney. To facilitate further exploration of gene specificity in mice, we have also developed a comprehensive specificity database, along with a web interface, API and MCP server. Extending ember to a human PBMC dataset collected from 255 diverse individuals, we find that variation in PBMCs is largely localized to classical monocytes. We also find genes with unique specificity by sex, age and ancestral background. Together, these applications establish ember as a powerful tool and provide a roadmap for elucidating the impact of human genetic variation using the murine model.

bioinformatics↗

Systematic cell-type resolved transcriptomes of 8 tissues in 8 lab and wild-derived mouse strains captures global and local expression variation

Mapping the impact of genomic variation on gene expression facilitates an understanding of the molecular basis of complex phenotypic traits and disease predisposition. Mouse models provide a controlled and reproducible framework for capturing the breadth of genomic variation observed in different genotypes across a wide variety of tissues. As part of the IGVF consortiums effort to catalog the effects of genetic variation, we uniformly characterized the transcriptomes of eight tissues from each mouse founder strain used to derive the Collaborative Cross strains, comprising five classical laboratory inbred strains and three wild-derived inbred strains. We sequenced samples from four male and four female replicates per tissue using single-nucleus RNA-seq to generate an "8-cube" dataset of 5.2 million nuclei across 106 cell types and cell states. As expected, the overall extent of transcriptome variation correlates positively with genetic divergence across the strains with the greatest differential between PWK/PhJ and CAST/EiJ. At the individual tissue level, heart and brain are relatively more similar across strains compared with gonads, adrenal, skeletal muscle, kidney, and liver. Further analyses revealed substantial strain variation, often concentrated in a few cell types as well as cell-state signatures that especially reflect strain-associated immune and metabolic trait differences. The founder 8-cube dataset provides rich transcriptome variation signatures to help explain strain-specific phenotypic traits and disease states, as illustrated by examples in tissue-resident immune cells, muscle degeneration, kidney sex differences, and the hypothalamicpituitary-adrenal axis. This data further provides a systematic foundation for the analysis of these tissues in the founder strains as well as the Collaborative Cross.

genomics↗