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Genetic analysis of blood pressure in 8 mouse intercross populations.

ABSTRACT: The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. We identified 14 blood pressure QTL in these populations, including > or =7 regions of the mouse genome not linked previously to blood pressure. Many QTL were detected in multiple crosses, either within our study or in studies published previously, which facilitates the use of bioinformatics methods to narrow the QTL and focus the search for candidate genes. The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control. These results greatly expand our knowledge of the genomic regions underlying blood pressure regulation in mice and support future studies to identify the causal genes within these QTL intervals.

SUBMITTER: Feng M

PROVIDER: S-EPMC2854560 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Genetic analysis of blood pressure in 8 mouse intercross populations.

Feng Minjie M Deerhake Marion E ME Keating Ryan R Thaisz Jill J Xu Lingfei L Tsaih Shirng-Wern SW Smith Randy R Ishige Taiichiro T Sugiyama Fumihiro F Churchill Gary A GA DiPetrillo Keith K

Hypertension (Dallas, Tex. : 1979) 20090803 4

The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. ...[more]

PMID: 19652078

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Project description:While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 [Berlin Fat Mouse Inbred (BFMI)]. A total of 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays. TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data were used to test for overrepresentation of nonsynonymous SNPs (nsSNPs) in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. A total of 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more nsSNPs than randomly selected regions (182 vs 125.9 ± 17.0, P < 1 × 10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions [P(BF) < 0.05]. Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6, and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of nsSNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

Dataset Information

Genetic analysis of blood pressure in 8 mouse intercross populations.

Publications

Genetic analysis of blood pressure in 8 mouse intercross populations.

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