Vertical selection for nuclear and mitochondrial genomes shapes gut microbiota and modifies risks for complex...

Area of Science:

• Genetics and Genomics
• Microbiology
• Systems Biology

Background:

• Complex disease heritability is traditionally linked to nuclear and mitochondrial genomes.
• The role of the microbiome in inherited disease susceptibility is increasingly recognized.

Purpose of the Study:

• To investigate the microbiome's contribution to the heritability of complex disease traits.
• To establish and analyze novel rat holobiont models incorporating varying nuclear, mitochondrial, and microbiomes.

Main Methods:

• Utilized selectively bred low capacity runner/high capacity runner (LCR/HCR) rats.
• Developed four rat holobiont models with matched and mismatched nuclear and mitochondrial genomes.
• Assessed polygenic disease risk and correlated it with microbiome composition and acquisition patterns.

Main Results:

• Differential microbiome acquisition was observed across holobiont models with varying genomes.
• Nuclear-mitochondrial-microbiotal interactions significantly correlated with increased adiposity, hypertension, cardiac dysfunction, and memory impairment.
• These interactions were identified as key reporters of disease susceptibility, not exercise capacity.

Conclusions:

• The microbiome is a critical third component, alongside nuclear and mitochondrial genomes, influencing complex disease heritability.
• Coselection of the microbiome with host genomes is a significant factor in disease susceptibility.
• Findings broaden the understanding of genetic and environmental interactions in complex diseases.