Collaborative Cross Mice Yield Genetic Modifiers for Pseudomonas aeruginosa Infection in Human Lung Disease.

MBio
Nicola Ivan LorèAlessandra Bragonzi

Abstract

Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (M...Continue Reading

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Citations

Oct 28, 2020·Nature Protocols·Channabasavaiah B GurumurthyMasato Ohtsuka
Oct 3, 2020·Trends in Microbiology·Jeffrey S BourgeoisDennis C Ko

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Methods Mentioned

BETA
Exome Sequencing
genotyping

Software Mentioned

Synteny
R Development Core Team
R
KING
EIGENSOFT
HAPPY
. HBREM
R glm
GEC
R package HAPPY

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