Saravanan, K. | bioRxiv Science

bioRxiv2025

Are Different Populations Fairly Represented in Single-Cell Omic Atlases?

Single-cell Omic atlases are transforming biology and medicine, yet their demographic representativeness has not been systematically evaluated. We analyzed >13,500 samples from the Human Cell Atlas (HCA), Human Tumor Atlas Network (HTAN), and PsychAD Consortium. Benchmarking against global and US general and disease-prevalence data, we found a striking, pervasive European over-representation and under-representation of Asian and Latino individuals. Nearly 70% of HCA samples lacked ancestry annotation, and among annotated samples, Europeans were over-represented sixfold. PsychAD was nearly two-thirds European. HTAN tumors were 69% European, with several cancer types showing sex skews beyond expected incidence. These disparities highlight that current single-cell resources risk embedding inequities into AI foundational models, biomarker discovery, and therapeutic development. We contextualize these findings within the structural, economic, and regulatory, survey the growing ecosystem of diversity-focused initiatives, and provide an actionable, field-specific checklist to help research teams design single-cell studies whose benefits extend equitably across populations.

genomics↗

bioRxiv2025

Early responses to hyperosmotic stress at the yeast vacuole

In yeast, early adaptation to hyperosmotic stress involves organelle-based mechanisms, including synthesis of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) at the vacuole. This low- level signaling lipid drives vacuolar fragmentation and activates the V-ATPase proton pump, which acidifies the vacuole and drives salt sequestration. The vacuole-resident V-ATPase subunit Vph1 interacts with PI(3,5)P2 via its N-terminal domain (Vph1NT), directly linking lipid signaling to proton pump regulation. Under NaCl stress, PI(3,5)P2 rapidly accumulates, triggering increased V-ATPase activity and vacuolar remodeling; these responses are impaired by deficient PI(3,5)P2 synthesis. A Vph1NT-GFP fusion protein with no membrane domain is cytosolic without salt, but upon NaCl addition, rapidly relocalizes to a region adjacent to the vacuole in a PI(3,5)P2- dependent manner. The intensity and duration of this response depend on salt concentration. Vph1NT-GFP returns to the same location upon repeated salt challenge, suggesting that PI(3,5)P2 synthesis occurs at a localized domain/contact site. Disrupting PI(3,5)P2 signaling, V- ATPase activity, or the high osmolarity glycerol pathway, which coordinates long-term transcriptional changes, compromises cellular adaptation to salt, underscoring the integration of lipid signaling and transcriptional regulation in hyperosmotic stress. These findings suggest activation of the V-ATPase, and possibly other targets, by PI(3,5)P2 synthesis provides immediate protection that primes cells for longer-term survival strategies. Significance Statement--Adaptation to high salt involves early responses at organelle membranes and slower transcriptional responses. The vacuolar/lysosomal signaling lipid, PI(3,5)P2 is critical for the early response, but the timing, localization, and targets of salt-induced PI(3,5)P2 synthesis are not fully understood. --Experiments using Vph1NT-GFP as a low-affinity PI(3,5)P2 biosensor suggest lipid synthesis occurs at a specific domain of the vacuolar membrane, with the level and duration of synthesis dependent on salt concentration and V-ATPase activity. A hog1{Delta} mutation ablates the slower response but elevates and extends PI(3,5)P2 activation. --Controlled PI(3,5)P2 synthesis at the vacuole supports V-ATPase-driven salt sequestration; long-term adaptation requires both V-ATPases and the HOG pathway.

cell biology↗