What makes some identical twins look and behave differently?

Metastable epialleles may sound like complex science, but they help explain why identical animals can still look and act differently. For years, scientists asked why two mice with identical DNA could differ, with one obese and yellow, the other lean and brown. This strange difference stems from epigenetics — changes in gene activity that don’t come from changes in the DNA sequence.

Over twenty years ago, scientists noticed something unusual while studying a mouse strain called agouti viable yellow, or Avy. Some of these genetically identical mice became yellow and obese, while others stayed brown and lean. The genes weren’t different, but gene expression was — driven by DNA methylation, small tags added to DNA during development.

In 2003, researchers found that giving pregnant mice nutrients like folate and B12 could affect methylation in their offspring. This increased methylation led more of the pups to develop brown coats and healthier weights.

The study showed a strong link between maternal diet and epigenetic change passed to the next generation. The Avy gene controls the changes in color and weight and is known as a metastable epiallele. Its methylation is set randomly during early development and then remains the same across all tissues for life.

Since then, researchers have asked how many metastable epialleles — or MEs — exist in mice. Could they help explain other unexpected differences in lab animals with identical genes? A recent study finally answers this question using the full mouse genome.

Dr. Robert A. Waterland at Baylor College of Medicine led the research, published in Nucleic Acids Research. His team searched the mouse genome for these rare and unpredictable epigenetic sites. Their results shocked many researchers: metastable epialleles are extremely rare.

To study MEs, the team used deep whole-genome bisulfite sequencing to map DNA methylation in detail. They examined three tissues — brain, kidney, and liver — in ten mice from the same inbred C57BL/6J strain. These mice were genetically identical, so any differences in methylation had to come from epigenetic factors.

The scientists searched for methylation patterns that were consistent in each mouse but varied between different mice. This pattern defines metastable epialleles — consistent across tissues but different between individuals. After scanning millions of sites, the researchers found only 29 that matched their criteria.

Dr. Chathura J. Gunasekara, a co-first author and bioinformatics expert, explained the study’s approach and surprising result. “We performed a comprehensive, unbiased scan of epigenetic variation across the entire mouse genome… only 29 metastable epialleles,” he said.

For years, scientists believed maternal nutrition could change methylation at MEs, as seen in the 2003 Avy study. Waterland’s new study suggests this isn’t true for most metastable epialleles. The team tested nutrients like folate and B12 that support methylation in developing embryos. They saw no changes in methylation at the 29 MEs they identified.

“Another surprising finding was that maternal diet… had no effect,” said co-author Uditha Maduranga, a bioinformatics analyst on the project. This challenges the idea that methyl donor supplements always influence methylation at epigenetic sites. The finding matters because it shows the Avy gene may be unusual, not typical of other metastable epialleles. Most MEs seem to set methylation randomly during development and remain mostly unaffected by the mother’s diet.

Most of the 29 metastable epialleles were linked to IAPs — or intracisternal A-particle elements — a kind of transposon. These “jumping genes” can move to new locations in the genome and change gene regulation. The MEs tended to occur at the beginning of IAP elements, suggesting a region of increased sensitivity.

The team also found methylation differences linked to the sex of the mouse, even before sex organs developed. These early methylation patterns may explain later differences in disease risk between males and females. Some methylation differences were shaped by transcription factors like CTCF and KRAB zinc finger proteins. These molecules help control when and how genes are turned on or off during development. They may play key roles in forming and preserving methylation patterns at sensitive genome sites.

While the team found just 29 MEs in mice, earlier studies revealed over 10,000 similar regions in humans. These human regions are called CoRSIVs — correlated regions of systemic interindividual variation. Most CoRSIVs link to genetic variation and don’t qualify as true metastable epialleles.

Still, they show strong sensitivity to early embryo environments and have been linked to human diseases. “Ironically,” said Waterland, “establishment of DNA methylation at human CoRSIVs is very sensitive… just like at the Avy metastable epiallele.” “In addition, CoRSIVs are strongly implicated in human disease,” he added.

The contrast between mice and humans raises questions about how good mouse models really are for human epigenetics. Waterland believes that using outbred mice — which have more genetic variety — would better reflect human variation. This study adds an important piece to understanding how early development influences lifelong gene expression and health.

Waterland’s findings suggest scientists should reconsider which animal models work best for studying human epigenetics. “Rather than the inbred mice used in biomedical research for decades,” he said, “outbred mice are likely a better model.”

This study answers one long-standing question but opens several new ones. Why are MEs so rare in inbred mice but so common in human data? How do transcription factors and development conditions combine to lock in methylation patterns for life?

Can scientists someday use this knowledge to predict or prevent diseases linked to early epigenetic changes? These are critical questions for future research. For now, Waterland’s study offers clearer insight into how epigenetic variation forms — and how we might study it next.

Note: The article above provided above by The Brighter Side of News.

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