Fig. 2: Triplication of the Ifnr locus contributes to global dysregulation of gene expression in a mouse model of DS.
a, Top—diagram indicating genomic locations of the mouse Ifnr gene cluster on MMU16 and gRNAs (orange arrowheads) employed for genome editing using CRIPSR–Cas9 technology. Positions are indicated in base pairs (bp) for the GRCm38 assembly of the M. musculus genome. Bottom—copy number variant analysis from WGS for a candidate founder (F0) bearing a deletion relative to a WT control. b, Breeding strategy to correct copy number of the Ifnr gene cluster in the Dp16 mouse model of DS. c, Volcano plots showing transcriptome analysis of mesenteric lymph nodes obtained from naïve adult WT (n = 5, 2 male and 3 female), Dp16 (n = 6, 3 male and 3 female), and Dp162xIfnrs (n = 6, 3 male and 3 female), highlighting expression of Ifnrs (red), other MMU16 genes triplicated in Dp16 (blue), with DEGs encoded elsewhere in the genome in gray, and all other genes in black. d, Expression levels in RPKM for representative MMU16-encoded mRNAs from mesenteric lymph nodes. q Values defined by DEseq2 after Benjamini–Hochberg correction. e, Scatter plots comparing mRNA fold-changes for Dp16 DEGs in mesenteric lymph nodes (top, sample sizes as in c) and brain (bottom, WT (n = 6, 2 male and 4 female), Dp16 (n = 5, 2 male and 3 female), and Dp162xIfnrs (n = 7, 4 male and 3 female)) for Dp16/WT and Dp162xIfnrs/WT, with Ifnrs highlighted in red, Dp16 triplicated genes in blue, nontriplicated Dp16 DEGs in gray, and slope (m) colored accordingly. Solid gray lines represent linear fits for the nontriplicated Dp16 DEGs. f, Sina plots displaying absolute fold-changes for DEGs triplicated in Dp16 (blue, excluding the four Ifnrs), and nontriplicated Dp16 DEGs (gray) across the genome for Dp16 versus WT or Dp162xIfnrs, comparisons, with P values for two-sided paired Wilcoxon rank tests, boxes representing interquartile ranges and medians, and notches approximating 95% CIs. gRNA, guide RNA.
