For more than a century, biology has been guided by the principles of inheritance first described by Gregor Mendel through his famous pea plant experiments. While those rules explain how many genetic traits are passed from parents to offspring, scientists have also known that DNA sequences are not the whole story.
In addition to genes themselves, parents can pass along epigenetic changes. These are chemical modifications that affect how genes function without altering the underlying DNA code.
Now, a new federally funded study in mice suggests that some of these inherited epigenetic marks do not follow Mendel’s classic laws. Researchers found that about 7% of the epigenetic inheritance patterns they examined behaved in unexpected ways. The study also uncovered rare forms of inheritance previously seen in plants and flies but not in mammals.
“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,” says Andrew Feinberg, M.D., Bloomberg Distinguished Professor in the Johns Hopkins University School of Medicine, Whiting School of Engineering and Bloomberg School of Public Health, and co-leader of the research with colleagues at Texas A&M University.
The findings were published May 20 in Nature Genetics and highlighted in an accompanying Nature brief. The work was supported by the National Institutes of Health and the National Science Foundation.
How Mendel’s Laws Explain Inheritance
Mendel’s laws describe how different versions of genes, known as alleles, are passed from one generation to the next. In mammals, offspring inherit one allele from each parent. Some alleles are dominant, meaning their traits are expressed, while others are recessive and remain hidden when paired with a dominant allele.
These principles have formed the foundation of modern genetics. However, scientists have already identified exceptions involving epigenetic mechanisms such as genomic imprinting. In those cases, whether an allele is active can depend on whether it was inherited from the mother or the father rather than whether it is dominant or recessive.
The new study uncovered additional examples of genomic imprinting and several other forms of inheritance that do not fit Mendel’s traditional framework.
New Evidence for Non-Mendelian Epigenetic Inheritance
In genomic imprinting, an allele can be chemically marked through a process called methylation and effectively switched off. These marks can originate in either sperm or egg cells and are passed to offspring.
The researchers identified imprinting in five additional genes.
Beyond those findings, the team discovered that non-Mendelian epigenetic inheritance may occur more often than previously recognized. They also found inherited epigenetic patterns that could not be traced back to either parent.
To investigate these effects, scientists tracked DNA methylation, a common epigenetic modification in which chemical groups containing carbon and hydrogen atoms attach to promoter regions that regulate whether genes are turned on or off.
The study examined tissue samples from three generations of mice between 4 and 6 months of age. The first generation included 26 mice, followed by 34 offspring in the second generation and 19 animals in the third generation.
Researchers analyzed large portions of the mouse genome, monitoring both genetic sequences and 12 previously recognized patterns of inherited DNA methylation.
The project brought together investigators from Johns Hopkins University and Texas A&M University. Feinberg worked alongside co-corresponding authors David Threadgill, Ph.D., Regents professor at Texas A&M, and Kasper Hansen, Ph.D., professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health. Johns Hopkins graduate student Adam Davidovich helped develop new laboratory and computational approaches that allowed genomic and methylation data to be studied simultaneously.
Traits That Appeared Without Parental Marks
Across the dataset, researchers identified 522 cases, representing about 7% of the epigenetic inheritance patterns examined on non-sex chromosomes, that did not follow Mendelian expectations.
Among these were 54 rare or “emergent” inheritance events that were absent in both parents.
In one example, two mice lacking methylation on a specific allele produced offspring in which both copies of that allele carried methylation.
“The methylation seemingly appeared out of nowhere,” says Feinberg.
These findings suggest that some epigenetic traits may emerge in descendants through mechanisms that remain poorly understood.
First Evidence of Paramutation in a Mammal
The study also revealed a rare inheritance phenomenon known as paramutation in a gene called Capn11, which plays an important role in normal sperm development. Changes in the human version of this gene have been linked to infertility and sperm-related disorders.
Paramutation occurs when methylation present on one allele triggers methylation on another allele.
“It’s almost like the methylation is transferred to another allele,” says Feinberg.
The paramutation was found in a region associated with a repetitive genetic element known to be influenced by environmental exposure. Researchers note that epigenetic changes have previously been connected to factors such as diet, stress, and trauma.
Implications for Human Health and Disease
According to Hansen, the findings highlight the value of studying both genetics and epigenetics together when investigating inherited traits and disease risk.
“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,” says Hansen.
To conduct the research, the team relied on long-read DNA sequencing technology, which can analyze DNA segments ranging from about 10,000 base pairs to more than one million base pairs in length. Although more labor-intensive than short-read sequencing, the technique provides a clearer picture of allele differences and distant methylation sites.
Looking ahead, the researchers plan to investigate similar inheritance patterns in human genomic data. Such studies could help clinical geneticists better understand inherited diseases and reveal how environmental influences, including diet, may affect epigenetic inheritance across generations.
Other authors on the study include Danila Cuomo and Alexandra Naron from Texas A&M University; Hang Su and Leonard McMillan from the University of North Carolina at Chapel Hill; and Sandeep Kambhampati, Qingqing Gong and Rakel Tryggvadottir from Johns Hopkins.
Funding for the research was provided by the National Institutes of Health (DP1DK119129, R35GM149323, RM1HG008529, R01DK130333), the National Science Foundation and a Texas A&M Health Science Center Seedling Grant.
