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. 2019 Jun 25;8:e43966. doi: 10.7554/eLife.43966

Figure 9. Dissection of strain-specific pathology.

Figure 9.

(A) SDA component 38 is comprised largely of genes on the X chromosome, with a gene loading direction that indicates failure of X inactivation. As illustrated by the cell scores (loadings) for this component, it is restricted to Hormad1-/- cells. (B) Pseudotime analysis indicates that Hormad1-/- cells diverge developmentally from all other strains around leptotene/zygotene. In this illustration, the X-linked gene Rhox2h is shown to have low or no expression in all cells prior to meiosis, and then rapidly increased expression specifically in Hormad1-/- cells until this lineage arrests. (C) Component 25 is the component most strongly enriched for Cul4a-/- cells. (D) We identified six components with shared enrichment for both Mlh3-/- and Hormad1-/- cells; these components contained genes with numerous significant GO associations related to Alzheimer’s disease (AD) pathology (main text, Figure 8B). For each SDA component, we tested for association between known AD genes and genes with either positive (P) or negative (N) loadings on that component. AD genes are highly enriched for expression in component 11, corresponding to macrophages. (E) Further investigation of protein expression of AD genes revealed APOE+ (green) cells within the tubules of Mlh3-/- and Hormad1-/- but not WT. These cells showed nuclear morphology different from native germ cells or Sertoli cells, and stain positive for the macrophage marker F4/80. The inset table summarizes raw data on the frequency of APOE+ tubules obtained by microscopy. The frequency of APOE+ tubules is more common in each mutant strain when compared to WT by Fisher’s exact test. Scale bar = 50 µm.