For more than a century, biology has been guided by the principles of heredity, first explained by Gregor Mendel through his famous pea experiment. These rules explain how many genetic traits are passed from parent to child, but scientists also knew that DNA sequence isn’t everything.
In addition to the genes themselves, parents can pass on epigenetic changes. These are chemical modifications that affect the function of genes without changing the underlying DNA code.
Now, a new federally funded study in mice suggests that some of these genetic epigenetic marks do not follow Mendel’s classical laws. Researchers found that about 7% of the epigenetic inheritance patterns they investigated behaved in unexpected ways. The study also uncovered a rare form of inheritance that had previously been seen in plants and flies, but not in mammals.
“Non-Mendelian patterns of epigenetic inheritance may be a faster way to acquire diverse and new traits than changing the genome sequence itself, especially in response to environmental pressures,” says Andrew Feinberg, MD, PhD, Bloomberg Distinguished Professor at the Johns Hopkins School of Medicine, Whiting School of Engineering, and Bloomberg School of Public Health, and co-leader of the study with colleagues at Texas A&M University.
The findings were published on May 20th. natural genetics And highlighted in the accompanying nature Easy. This research was supported by the National Institutes of Health and the National Science Foundation.
How do Mendel’s laws explain heredity?
Mendel’s laws explain 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 the trait is expressed, while other alleles are recessive, meaning they remain hidden when combined with a dominant allele.
These principles formed the basis of modern genetics. However, scientists have already identified exceptions involving epigenetic mechanisms such as genomic imprinting. In such cases, whether an allele is active may depend on whether it was inherited from the mother or father, rather than whether it is dominant or recessive.
New research reveals additional examples of genomic imprinting and several other forms of inheritance that do not fit into Mendel’s traditional framework.
New evidence for non-Mendelian epigenetic inheritance
Genomic imprinting allows alleles to be chemically marked through a process called methylation, effectively switching them off. These marks originate from sperm or egg cells and are passed on to offspring.
The researchers identified imprinting in five additional genes.
Beyond these findings, the team discovered that non-Mendelian epigenetic inheritance may occur more frequently than previously realized. They also discovered genetic epigenetic patterns that cannot be traced back to either parent.
To investigate these effects, the scientists tracked DNA methylation. DNA methylation is a common epigenetic modification in which chemical groups containing carbon and hydrogen atoms are attached to promoter regions that control turning genes on and off.
The study examined tissue samples from three generations of mice aged 4 to 6 months. The first generation included 26 mice, followed by the second generation with 34 progeny, and the third generation with 19 mice.
The researchers analyzed a large portion of the mouse genome, monitoring both gene sequences and 12 previously recognized patterns of genetic DNA methylation.
The project brought together researchers from Johns Hopkins University and Texas A&M University. Feinberg collaborated on the study with co-corresponding authors David Threadgill, Ph.D., a Regents professor at Texas A&M, and Kasper Hansen, Ph.D., a professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health. Johns Hopkins University graduate student Adam Davidovich helped develop new laboratory and computational approaches that allow genomic and methylation data to be studied simultaneously.
Characteristics that appeared without parent markings
Across the dataset, the researchers identified 522 cases that did not follow Mendel’s predictions, representing about 7% of the epigenetic inheritance patterns examined for non-sex chromosomes.
These included 54 rare or “emergency” inheritance events that were not present in both parents.
In one example, two mice lacking methylation of a particular allele produced offspring in which both copies of that allele were methylated.
“Methylation seemed to come out of nowhere,” Feinberg says.
These findings suggest that some epigenetic traits may appear in offspring through mechanisms that are not yet well understood.
First evidence of paramutation in mammals
The study also revealed a rare genetic phenomenon known as paramutation in a gene called . captain 11plays an important role in normal sperm development. Changes in the human version of this gene are thought to be associated with infertility and sperm-related diseases.
Paramutation occurs when methylation present on one allele causes methylation on another allele.
“It’s almost like the methylation was transferred to a different allele,” Feinberg says.
This paramutation was found in regions associated with repetitive genetic elements known to be influenced by environmental exposures. Researchers note that epigenetic changes have previously been linked to factors such as diet, stress, and trauma.
Impact on human health and disease
Hansen said the findings highlight the value of studying both genetics and epigenetics together when investigating inherited traits and disease risk.
“This work may persuade scientists to more frequently integrate both genomics and epigenomics to fully understand how traits that produce disease and health are inherited,” Hansen says.
To conduct the study, the team relied on long-read DNA sequencing technology, which can analyze DNA segments ranging from about 10,000 base pairs to more than 1 million bases in length. Although this technique is more labor-intensive than short-read sequencing, it provides a clearer picture of allelic differences and distant methylation sites.
Looking ahead, the researchers plan to investigate similar inheritance patterns in human genome data. Such studies could help clinical geneticists better understand inherited diseases and reveal how environmental influences, including diet, influence epigenetic inheritance across generations.
Other authors of the study include Danila Cuomo and Alexandra Naron of Texas A&M University. Hang Hsu and Leonard McMillan of the University of North Carolina at Chapel Hill; Sandeep Khambampati, Chin-Ching Gong, and Raquel Trygvadottir of Johns Hopkins University;
Funding for the study was provided by the National Institutes of Health (DP1DK119129, R35GM149323, RM1HG008529, R01DK130333), the National Science Foundation, and Texas A&M Health Science Center Seedling Grants.
