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Retention of ES cell-derived 129 genome drives NLRP1 hypersensitivity and gene expression changes in Nlrp3-/- mice

ABSTRACT: Immune response genes are disproportionately polymorphic in humans and mice, with heterogeneity amongst loci driving strain specific host defense responses. The inadvertent retention of polymorphic loci can confound results, lead to false conclusions, and delay scientific progress. By combining RNAseq and variant calling analyses, we identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency. We show that 129S NLRP1 can be tolerated at higher expression levels at steady-state, however this sensitizes Nlrp3-/- mice to NLRP1 inflammasome activation. Furthermore, the presence of 129S genome leads to altered gene and protein regulation across multiple cell-types, including of the key tissue-resident macrophage marker, TIM4. In order to resolve NLRP3 dependent phenotypes we validate a conditional Nlrp3 allele enabling temporal and cell-type specific control of NLRP3 deletion. Our study provides an accessible strategy to identify functionally relevant SNPs and assess genomic contamination in transgenic mice, to allow for unambiguous attribution of phenotypes to the target gene.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Anshupa Sahu

PROVIDER: E-MTAB-13601 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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