Gene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line

Area of Science:

• Genetics
• Environmental Science
• Immunology

Background:

• Phenotypic variation arises from gene-environment interactions, but their specific impact remains largely unknown.
• Understanding these interactions is crucial for deciphering complex traits and diseases.

Purpose of the Study:

• To investigate the influence of diet on phenotypic variation and genetic susceptibility in an autoimmunity-prone mouse model.
• To identify specific genes and pathways affected by gene-environment interactions.
• To explore the role of diet in modulating genetic predisposition to autoimmune diseases like lupus.

Main Methods:

• Feeding three distinct diets to 1154 mice from an autoimmunity-prone intercross line (AIL).
• Performing whole-genome sequencing on AIL founder strains to identify quantitative trait loci (QTL).
• Administering similar dietary regimens to NZM2410/J mice to assess diet's effect on lupus predisposition.
• Analyzing changes in intestinal bacterial and fungal communities.

Main Results:

• Diet substantially contributes to the variability of complex traits and unmasks additional genetic susceptibility QTL.
• Whole-genome sequencing resolved QTLs to a few or single candidate genes.
• Diet modifies genetic susceptibility to lupus in NZM2410/J mice.
• Dietary changes shift intestinal microbial composition preceding clinical disease manifestation.

Conclusions:

• Environmental factors, particularly diet, play a critical role in modulating genetic susceptibility and phenotypic variation.
• Including environmental factors in genetic association studies is essential for a comprehensive understanding of disease.
• Dietary interventions may offer therapeutic strategies for autoimmune diseases by altering genetic predisposition and gut microbiome.