For over a century, Gregor Mendel’s pea plant experiments have served as the holy text of genetics - a tidy story of dominant and recessive alleles passed down like family heirlooms. But as it turns out, DNA isn’t the only thing parents can bequeath. A new federally funded study in mice reveals that epigenetic marks - chemical modifications that tweak gene function without altering the underlying code - can break Mendel’s classic rules. About 7% of the epigenetic inheritance patterns examined didn’t behave as expected, and the team even spotted rare inheritance phenomena previously seen only in plants and flies.
“Non-Mendelian patterns of inheriting epigenetics could be a faster way to acquire diverse or new traits than alterations in the genomic sequence itself, especially in response to environmental pressures,” said Andrew Feinberg, M.D., a Bloomberg Distinguished Professor at Johns Hopkins University and co-leader of the research with colleagues at Texas A&M University. The findings, published May 20 in *Nature Genetics* and backed by the National Institutes of Health and the National Science Foundation, add fresh wrinkles to the tidy picture Mendel painted with his peas.
Mendel’s laws describe how alleles - different versions of genes - are inherited, with dominant ones expressing traits and recessive ones hiding out until they get a matching partner. But scientists already knew exceptions existed, like genomic imprinting, where whether an allele is active depends on which parent it came from. The new study uncovered imprinting in five additional genes and found that non-Mendelian epigenetic inheritance may be more common than previously thought. In some cases, inherited epigenetic patterns couldn’t be traced back to either parent - epigenetic ghosts, if you will.
To track these effects, researchers analyzed DNA methylation - a common epigenetic modification where carbon-and-hydrogen chemical groups attach to gene promoter regions - in tissue samples from three generations of mice (26 in the first, 34 in the second, 19 in the third). They monitored both genetic sequences and 12 known patterns of inherited methylation, using long-read DNA sequencing to get a clearer picture of allele differences and distant methylation sites.
Across non-sex chromosomes, the team identified 522 cases - about 7% of the patterns examined - that defied Mendelian expectations. Among these were 54 “emergent” inheritance events absent in both parents. In one striking example, two mice lacking methylation on a specific allele produced offspring where both copies of that allele carried methylation. “The methylation seemingly appeared out of nowhere,” said Feinberg. The study also found the first evidence of paramutation in a mammal: in a gene called Capn11, which plays a key role in sperm development, methylation on one allele triggered methylation on another. “It’s almost like the methylation is transferred to another allele,” Feinberg explained. The paramutation occurred in a region linked to a repetitive genetic element known to be influenced by environmental factors like diet, stress, and trauma.
“This work may convince scientists to integrate both genomics and epigenomics more often for a complete understanding of how traits that produce disease and healthy states are inherited,” said co-author Kasper Hansen, Ph.D., professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health. The team now plans to hunt for similar patterns in human genomic data, which could help clinical geneticists understand inherited diseases and how environmental influences ripple across generations.