Beyond DNA: Scientists Discover Inheritance That Breaks the Rules of Genetics

Scientists found that some inherited traits can bypass the traditional rules of genetics, revealing a surprising new layer of inheritance beyond DNA.

For more than a century, Gregor Mendel’s laws of inheritance have served as the foundation of genetics. But new research suggests that inheritance can be more complicated than the DNA sequences passed from parents to their children.

In a federally funded study involving mice, scientists found that certain inherited epigenetic marks, which are chemical modifications that influence gene activity without altering the underlying DNA code, can be transmitted across generations in ways that do not follow Mendel’s classic rules. The researchers estimate that about 7% of the epigenetic inheritance patterns they examined fell outside traditional Mendelian expectations.

The findings also revealed rare forms of inheritance that had not previously been documented in mammals, including a naturally occurring example of paramutation, a phenomenon previously observed in plants and fruit 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,” 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 study was published in Nature Genetics and was supported by the National Institutes of Health and the National Science Foundation.

Looking Beyond Mendel’s Laws

Mendel’s laws describe how different versions of genes, known as alleles, are inherited. These principles explain how dominant and recessive traits are passed from one generation to the next. In mammals, offspring inherit one allele from each parent, and dominant alleles generally determine which traits are expressed.

Scientists have long known that some inherited effects fall outside those rules. One example is genomic imprinting, in which chemical tags can silence a gene depending on whether it came from the mother or father. In these cases, gene activity is controlled by the parent of origin rather than by whether the allele is dominant or recessive.

The new study identified imprinting in five additional genes. More importantly, it suggested that non-Mendelian epigenetic inheritance may occur more often than previously recognized.

Researchers also observed inherited epigenetic patterns in offspring that were not detected in either parent, an unexpected result that challenges conventional assumptions about inheritance.

Tracking Epigenetic Changes Across Generations

The team focused on DNA methylation, a common epigenetic modification in which chemical groups containing carbon and hydrogen atoms attach to promoter regions of genes. These promoter regions help control whether a gene is switched on or off.

To investigate how methylation is inherited, scientists analyzed tissue samples from three generations of mice between 4 and 6 months of age. The study included 26 mice in the first generation, 34 offspring in the second generation, and 19 mice in the third generation.

Researchers examined large portions of the mouse genome and tracked both genetic variation and 12 known inheritance patterns involving DNA methylation.

Feinberg collaborated with co-corresponding authors David Threadgill, Ph.D., Regents professor at Texas A&M University, and Kasper Hansen, Ph.D., professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health. Together with Johns Hopkins graduate student Adam Davidovich, the team developed new laboratory and computational methods that allowed them to analyze genomic and methylation data simultaneously.

Surprising Cases of Inheritance

Across the study, the researchers identified 522 cases, representing approximately 7% of epigenetic inheritance patterns, in which methylation on non-sex chromosomes was inherited in ways that did not conform to Mendel’s laws.

Among those were 54 rare or “emergent” inheritance events that appeared in offspring even though neither parent showed the same methylation pattern.

For example, when two mice lacking methylation on a specific allele were bred, researchers sometimes observed offspring with methylation on both copies of that allele.

“The methylation seemingly appeared out of nowhere,” says Feinberg.

The team also identified a naturally occurring example of paramutation in a mammalian gene called Capn11, which plays a role in normal sperm development through calcium-dependent regulation. Mutations affecting the human version of the gene are linked to infertility and sperm abnormalities.

Paramutation occurs when methylation associated with one allele triggers methylation in another allele. The researchers found this effect in a region containing a repetitive genetic element known to be sensitive to environmental influences.

“It’s almost like the methylation is transferred to another allele,” says Feinberg.

Previous studies have linked epigenetic changes to environmental factors including stress, trauma, and diet.

Implications for Human Health and Disease

The findings suggest that scientists may need to consider both genetic and epigenetic information to fully understand how traits, diseases, and health outcomes are inherited.

“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 carry out the study, researchers relied on long-read DNA sequencing technology, which can analyze DNA fragments 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 is better suited for identifying differences between alleles and detecting methylation sites located far from the main body of a gene.

The researchers plan to extend their work to human genomic data. Future studies could help scientists better understand unusual inheritance patterns in families affected by disease and provide new insight into how environmental factors such as diet may influence inheritance across generations.

References:

“Non-Mendelian inheritance of DNA methylation patterns in mice” by Adam Davidovich, Danila Cuomo, Hang Su, Sandeep Kambhampati, Qingqing Gong, Alexandra Naron, Rakel Tryggvadottir, Leonard McMillan, Kasper D. Hansen, David W. Threadgill and Andrew P. Feinberg, 20 May 2026, Nature Genetics.
DOI: 10.1038/s41588-026-02604-z

“Allele-specific methylation uncovers non-Mendelian inheritance,” 21 May 2026, Nature Genetics.
DOI: 10.1038/s41588-026-02603-0

Additional 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 University.

Funding 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.

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