Scientists have long known that the DNA code in genes is not the only way to pass genetic traits from parents to offspring. "Epigenetic" marks — chemical modifications to DNA that don't change the DNA code itself — can also be passed down.
Now, a new federally funded study using mice reveals that some of those marks — about 7% of them — can be inherited in ways that break the century-long understanding of the rules of inheritance explored and recorded by Gregor Mendel's work with pea plants. The study also reveals new, unexpected examples of inheritance patterns that defy Mendel's law — such as a naturally occurring paramutation, seen previously in plants and flies, and 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 new study, funded by the National Institutes of Health and National Science Foundation, was reported May 20 in Nature Genetics, as well as an accompanying Nature brief.
The well-studied rules of genetic inheritance — known as Mendel's Laws — cover how genetic material known as alleles sort themselves, are dominant or recessive, and in what ways they get passed down to new generations. Alleles are variations on genes that lead to a specific trait or disease state. In mammals, one allele is inherited from each parent, and either of those alleles can be dominant or recessive.
The rules state, for example, that alleles in offspring are inherited from each parent, and the traits of dominant alleles prevail over recessive ones, which are silenced. Several previous studies have already shown that some patterns of epigenetic inheritance, such as genomic imprinting, can break the guiding principles established by the Austrian-born friar. The new study also found examples of genomic imprinting, but also other types of non-Mendelian patterns of epigenetic inheritance that surprised the scientists.
In examples of genomic imprinting, an allele in either parent can be labeled as coming from sperm or an egg and silenced by methylation. Such imprinted alleles are passed down to offspring and are silenced not because they are recessive but based on which parent contributes the imprinted allele. The new research found imprinting examples in five additional genes.
In addition to the new examples of genetic imprinting, results of the current study suggest that epigenetic patterns of inheritance that defy Mendel's rules may be more frequent than described in other studies. In addition, the research team found epigenetic patterns passed down to offspring that were not present in either parent.
For the study, researchers tracked how mice inherit a type of epigenetic change to DNA called methylation, in which chemical groups made up of carbon and hydrogen atoms are attached to the so-called promoter region of a gene, which turns it on or off.
The scientists sampled tissue from three generations of male and female mice at 4–6 months old: 26 in the first group, 34 offspring in the second generation and 19 in the third generation.
They scoured extensive parts of the mouse genome in each tissue sample, following how the genomic sequence and 12 known inherited patterns of DNA methylation were passed down in the three generations of mice.
Feinberg worked with 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. They worked with Johns Hopkins graduate student Adam Davidovich to develop new experimental and computational strategies to map methylation and genomic data together.
In all, the researchers found 522 instances — about 7% of epigenetic inheritance patterns — in which methylation was inherited on non-sex chromosomes in a variety of ways that broke Mendel's laws.
Some 54 of those instances represented rare or "emergent" types of epigenetic inheritance not present in either parent. For example, a cross between two mice with no methylation on the same allele, which should have resulted in a mouse that inherited no methylation on the allele, could instead result in a mouse with methylation on both alleles. "The methylation seemingly appeared out of nowhere," says Feinberg.
The scientists also found another rare type of inheritance called paramutation in a gene called Capn11, which encodes a calcium-dependent gene that regulates normal sperm development. Alterations in the human version of the gene cause infertility and problems with sperm.
Paramutation occurs when methylation in one allele leads to methylation in another allele. The paramutation was located in an area of the gene associated with a repetitive element of a type known to be influenced by environmental exposure. "It's almost like the methylation is transferred to another allele," says Feinberg. He notes that epigenetic influences on the genome have been tied to environmental pressures such as environmental stress, trauma and diet.
"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.
For their studies of the mouse genome, the research team used genomic sequencing involving "long-reads" of DNA segments that are between 10,000 pairs of chemical DNA letters up to more than a million chemical base pairs. Long-read sequencing is more labor-intensive, but it is better than short-read sequencing at identifying variations among alleles, as well as methylation spots that can be far away from the bulk of a gene.
Feinberg says they plan to study epigenetic inheritance patterns using human genomic data, as well. That work may provide more insights for tracking non-Mendelian patterns of epigenetic inheritance that can inform clinical geneticists looking for patterns of disease in families. It may also help scientists study how environmental factors, such as diet, influence epigenetic inheritance patterns.
Other scientists who authored the study are 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.
