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Transgenerational Epigenetic and Phenotypic Inheritance Across Five Generations in Sheep.

Mehmet Kizilaslan1, Camila U Braz2, Jessica Townsend1

  • 1Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

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|July 12, 2025
PubMed
Summary
This summary is machine-generated.

Methionine supplementation in sheep fathers (F0) led to lasting transgenerational epigenetic inheritance of traits in their descendants (F3 and F4). This dietary intervention influenced offspring phenotypes beyond the F2 generation.

Keywords:
DNA methylationenvironmental epigeneticsmethioninepaternal nutritionsheeptransgenerational epigenetic inheritance

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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.