Popko, N. | Search bioRxiv

bioRxiv2026

Evaluating Aggregated Gene Level eQTL Scores

Genetic feature engineering, used in methods such as transcriptome-wide association study, supports gene-trait association testing by aggregating single variants into gene-level features predictive of expression. To evaluate how different model architectures, LD filtering thresholds, and variant prioritization methods affect expression prediction quality, we trained over 3 million models and evaluated their performance in independent cohorts. Using the best performing models to impute expression and immunotherapy response as an example trait, we found a significant association with the reactive oxygen species pathway (p=0.032). Our model training workflow will support genetic feature engineering towards improved complex trait modeling.

bioinformatics↗

bioRxiv2025

Distinct causes of three phenotypic hallmarks of hematopoietic aging

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, HSC accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NF{kappa}B both responds to and directs inflammation, and we present an experimental model of elevated NF{kappa}B activity ("I{kappa}B-") to dissect its role in hematopoietic aging phenotypes. We found that while elevated NF{kappa}B activity is not sufficient for HSC accumulation, HSC-autonomous NF{kappa}B activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the I{kappa}B- proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A new scRNA-seq HSPC labeling framework enabled comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NF{kappa}B activity and quiescence, but not myeloid bias. These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable. SummaryAging is associated with inflammation and three hallmark hematopoietic dysfunctions. Using mouse models and single-cell analyses we report that each has a different cause: HSC accumulation is NF{kappa}B-independent, HSC functional impairment is driven by NF{kappa}B within HSCs, and myeloid bias is driven by the NF{kappa}B-altered milieu.

immunology↗