Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity

Ilona Binenbaum, Hanifa Abu Toamih Atamni, Georgios Fotakis, Georgia Kontogianni, Theodoros Koutsandreas, Eleftherios Pilalis, Richard Mott, Heinz Himmelbauer, Fuad A. Iraqi*, Aristotelis A. Chatziioannou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The Collaborative Cross (CC) mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. Results: We established an automated and reproducible integrative workflow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workflow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrated these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression differs significantly between obese and non-obese mice, with a significant sex effect, where male and female mice exhibit different responses and coping mechanisms. Conclusion: Integration of the data showed that different genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity are different in female and male mice. The clear distinction we observed in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

Original languageEnglish
Article number761
JournalBMC Genomics
Volume21
Issue number1
DOIs
StatePublished - 1 Dec 2020

Funding

FundersFunder number
7th Joint Translational Call
European Innovative Research and Technological Development Projects In NanomedicineEACEA/04/2017
German Israeli Science FoundationI-63-410.20-2017
Ministry Of Education, Research & Religious Affairs
State Scholarship Foundation in Greece
Wellcome Trust075491/Z/04, 090532/Z/09/Z, 085906/Z/08/Z
Seventh Framework Programme262055
German-Israeli Foundation for Scientific Research and Development
United States-Israel Binational Science Foundation2015077
State Scholarships Foundation
General Secretariat for Research and Technology
Israel Science Foundation429/09, 1085/18
Tel Aviv University
European Regional Development Fund

    Keywords

    • Collaborative Cross
    • High-fat diet
    • Obesity
    • QTL
    • RNAseq
    • Sex-differences

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