Vetr, N. G. | Search bioRxiv

bioRxiv2026

Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

systems biology↗

bioRxiv2025

Functional impact of rare variants and sex across the X-chromosome and autosomes

The human X-chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X-chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X-chromosome is understudied. To investigate functional rare variants on the X-chromosome, we use observations of outlier gene expression from GTEx consortium data. We show outlier genes are enriched for having nearby rare variants on the X-chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 753 rare variants in 449 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Combined, our study investigates functional rare variants on the X-chromosome, and further details how sex-stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.

genomics↗