Non-Mendelian inheritance of DNA methylation patterns in mice
TL;DR
Imagine your DNA is like a huge book of instructions. Mendel's laws are the normal rules for how chapters of that book get passed from parents to children. But there's also a layer of sticky notes on top of the book—called epigenetic marks—that tell cells which chapters to read and which to ignore. This study found that most of the time (about 93%), these sticky notes follow the normal inheritance rules. But about 7% of the time, they do something unexpected: new patterns appear that neither parent had, or a mark from one parent somehow silences the same mark from the other parent (called paramutation), or males and females end up with completely different sticky notes even when they inherit the same DNA. Scientists discovered this by using a new ultra-precise DNA reading technology in mice, and it opens the door to understanding hidden layers of how traits—and possibly diseases—are passed down through generations.
Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly understood. Here we developed a genome-wide approach to study epigenetic inheritance in mice using long-read nanopore sequencing. Using this approach in both liver and muscle, we found that ~93% of autosomal epigenetic inheritance patterns followed Mendel's laws, primarily driven by cis-acting methylation quantitative trait loci. However, we also identified extensive non-Mendelian inheritance, including emergent epigenetic inheritance patterns, widespread sex-specific DNA methylation patterns localized to the liver, and five seemingly new autosomal and X-linked imprinted genes. Notably, we also report an example of naturally occurring intergenerational paramutation, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c. Overall, an unexpectedly high ~7% of autosomal epigenetic inheritance patterns identified were non-Mendelian, highlighting the importance of epigenetic information in the analysis of inherited traits and disorders.
- 1Approximately 93% of autosomal epigenetic inheritance patterns followed Mendel's laws, primarily driven by cis-acting methylation quantitative trait loci (meQTLs).
- 2An unexpectedly high ~7% of autosomal epigenetic inheritance patterns were non-Mendelian, including emergent epigenetic inheritance and sex-specific DNA methylation patterns.
- 3Five seemingly new autosomal and X-linked imprinted genes were identified using long-read nanopore sequencing in mouse liver and muscle.
- 4A naturally occurring example of intergenerational paramutation was identified, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c.
- 5A genome-wide framework for studying epigenetic inheritance across generations was developed using long-read nanopore sequencing in Collaborative Cross mouse crosses.
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