Kidney Week

Abstract: FR-PO1204

Single-Cell Detection of Somatic Copy Number Alterations in Human Kidney by Chromatin Accessibility Profiling

Session Information

• CKD: Mechanisms - 2
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Chen, Xinyi Emilia, University of Pennsylvania Wharton School, Philadelphia, Pennsylvania, United States

Xinyi Emilia Chen

• Zhang, Nancy, University of Pennsylvania Wharton School, Philadelphia, Pennsylvania, United States

Nancy Zhang, PhD

• Wilson, Parker C., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Parker C. Wilson, MD, PhD

Background

Loss of Y chromosome (LOY) is the most common somatic chromosomal alteration (mCA) in men. Until recently, it was thought that LOY was unique to hematopoietic tissue, but it also occurs in the kidney and is enriched in injured proximal tubule (PT) cells – a cell state defined by a pro-inflammatory signature that predicts kidney function decline (Wilson et al. Genome Biology 2023). We hypothesize LOY is an indicator of genomic instability, however, LOY is not a perfect marker because the majority of injured PT cells do not have LOY and it is unclear if similar mCA occur in female cells.

Methods

We realigned and preprocessed single-cell multiome or single-cell ATAC (snATAC) datasets using SnapATAC2, integrated them with scvi-tools and annotated cell barcodes using established markers. To detect mCA, we modeled ATAC fragment coverage as a proxy of single-cell copy number. For our model, let Χ_ci be the fragment coverage of region i (which can be a chromosome arm) and cell c. We assume a negative-binomial model for the fragment coverage, Χ_ci ~ NB(α_c β_i γ_ci, Φ_ci) where α_c is the cell-specific library size, β_i is a region-specific background bias, and Φ_ci is a cell- and region-specific dispersion, to be estimated by the observed variance-mean relationship in the data. The parameter γ_ci, which captures the cell-specific fold enrichment/depletion of fragment coverage for region i, is an estimate of copy number state.

Results

We analyzed 526,903 kidney cells from 99 male or female donors with or without CKD. Injured PT (PT_VCAM1, PT_PROM1), endothelial cells (ENDO), fibroblasts (FIB_VSMC_MC) and mononuclear cells (MONO) had approximately two-fold higher proportion of LOY than other cell types (Figure 1A). mCA involving the X chromosome were enriched in some of the same cell types in women, but at a lower proportion than LOY (Figure 1B). Both LOY and X chromosome mCA were associated with an increased autosomal mCA burden.

Conclusion

Somatic mCA are enriched in specific kidney cell types and may provide insight into factors that drive CKD progression.

Funding

• NIDDK Support