Epigenetic changes to gene pathways linked to male fertility in ex situ black-footed ferrets

Stavi R. Tennenbaum, Robyn Bortner, Colleen Lynch, Rachel Santymire, Adrienne Crosier, Jenny Santiestevan, Paul Marinari, Budhan S. Pukazhenthi, Pierre Comizzoli, Melissa T.R. Hawkins, Jesús E. Maldonado, Klaus Peter Koepfli, Bridgett M. vonHoldt, Alexandra L. DeCandia

Research output: Contribution to journalArticlepeer-review

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Environmental variation can influence the reproductive success of species managed under human care and in the wild, yet the mechanisms underlying this phenomenon remain largely mysterious. Molecular mechanisms such as epigenetic modifiers are important in mediating the timing and progression of reproduction in humans and model organisms, but few studies have linked epigenetic variation to reproductive fitness in wildlife. Here, we investigated epigenetic variation in black-footed ferrets (Mustela nigripes), an endangered North American mammal reliant on ex situ management for survival and persistence in the wild. Despite similar levels of genetic diversity in human-managed and wild-born populations, individuals in ex situ facilities exhibit reproductive problems, such as poor sperm quality. Differences across these settings suggest that an environmentally driven decline in reproductive capacity may be occurring in this species. We examined the role of DNA methylation, one well-studied epigenetic modifier, in this emergent condition. We leveraged blood, testes, and semen samples from male black-footed ferrets bred in ex situ facilities and found tissue-type specificity in DNA methylation across the genome, although 1360 Gene Ontology terms associated with male average litter size shared functions across tissues. We then constructed gene networks of differentially methylated genomic sites associated with three different reproductive phenotypes to explore the putative biological impact of variation in DNA methylation. Sperm gene networks associated with average litter size and sperm count were functionally enriched for candidate genes involved in reproduction, development, and its regulation through transcriptional repression. We propose that DNA methylation plays an important role in regulating these reproductive phenotypes, thereby impacting the fertility of male ex situ individuals. Our results provide information into how DNA methylation may function in the alteration of reproductive pathways and phenotypes in artificial environments. These findings provide early insights to conservation hurdles faced in the protection of this rare species.

Original languageEnglish (US)
Article numbere13634
JournalEvolutionary Applications
Issue number1
StatePublished - Jan 2024

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • General Agricultural and Biological Sciences


  • DNA methylation
  • Mustela nigripes
  • conservation
  • infertility
  • reproduction
  • sperm


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