Transgenerational Epigenetic and Phenotypic Inheritance Across Five Generations in Sheep.

Area of Science:

• Epigenetics
• Livestock Science
• Nutritional Genomics

Background:

• Epigenetic information can be inherited across generations despite developmental reprogramming.
• Transgenerational epigenetic inheritance (TEI) of phenotypes is crucial but understudied, especially concerning dietary interventions in livestock.
• Few studies have investigated the long-term effects of nutritional interventions on epigenetic inheritance in farm animals.

Purpose of the Study:

• To investigate the transgenerational effects of methionine supplementation on epigenetic modifications and phenotypes in sheep.
• To identify differentially methylated genes (DMGs) exhibiting inheritance across multiple generations (F3 and F4).
• To correlate dietary intervention effects with inherited epigenetic changes and offspring phenotypes.

Main Methods:

• Whole-genome bisulfite sequencing (WGBS) for single-base resolution differential methylation analysis.
• Analysis of differentially methylated cytosines (DMCs) and differentially methylated genes (DMGs) in F3 and F4 generations.
• Comparison of epigenetic data from control and methionine-supplemented F0 twin-pair rams and their descendants.
• Estimation of the effect size of the F0 diet on F3 and F4 growth and fertility phenotypes.

Main Results:

• Identified 41 DMGs with transgenerational epigenetic inheritance (TEI-DMGs) across four generations and 11 TEI-DMGs across five generations.
• Detected significant differences in methylation patterns between control and methionine-supplemented lineages.
• Demonstrated a correlation between the F0 diet group, inherited differentially methylated genes, and offspring growth and fertility phenotypes in F3 and F4 generations.
• Provided evidence for long-lasting transgenerational effects of dietary intervention extending beyond the F2 generation.

Conclusions:

• A moderate dietary intervention (methionine supplementation) can induce persistent transgenerational epigenetic inheritance of phenotypes in sheep.
• This study provides the first gene-level and phenotypic evidence for long-lasting dietary effects on offspring phenotypes in sheep beyond the F2 generation.
• Methionine supplementation's impact on epigenetic markers and subsequent phenotypes highlights the potential for nutritional strategies to influence livestock health and productivity across generations.