Epigenetics research continuesWritten by Saige Albert
“How does a mammalian organism have a genome that varies in so many different ways, and how can we understand how that genome works to manipulate it, not only for biomedical purposes, but for production traits?” asked head of the Department of Genetics at North Carolina State University David Threadgill at the Beef Improvement Federation Conference in late April.
Threadgill continued that the agriculture industry has begun to commonly utilize DNA technology to continue to develop cattle herds, largely looking at the DNA sequence itself.
“The polymorphisms that are present in the genome of cattle have dramatically accelerated our ability to do a variety of things, like genomic selection, with a focus on the actual DNA variants to enhance certain qualities of cattle,” he noted. “There is another complimentary area taking off that focuses on the non-genetic aspects that can be inherited.”
Changes in DNA
In addition to changes in the DNA sequence, Threadgill marked epigenetic modifications of DNA, or molecules that have been added, but that have not changed the sequence itself, as being both important to gene expression.
He continued, noting that epigenetics looks at alterations to DNA that don’t affect the sequence itself.
“The term epigenetics was first coined in the early 1940s by Conrad Wattington,” said Threadgill. “He began to describe epigenetics as the field by which the genes and their products bring about phenotypic changes.”
Wattington’s work was carried out prior to the Watson and Crick discovery of the structure of DNA.
“Epigenetics comes from the Greek and means ‘above’ or ‘on top of’ genetics,” Threadgill added. “These aren’t changes or new polymorphisms, but added modifications to the existing sequence. The modifications occur above or on top of the genetic code and have inherited effects. They are transient and can be manipulated by manipulating the animals themselves.”
Without going to a molecular level, epigenetic marks can be influenced, making them potentially very valuable to producers.
While most epigenetic modifications are erased as new organisms are developing, some are added back, which enables the marks to be retained from generation to generation.
“We are starting to learn now that these can actually be inherited, and they can have very pronounced effects on subsequent generations,” he added.
From a production standpoint, Threadgill said that by harnessing this technology, producers may be able to alter certain characteristics very quickly, simply by modifying handling strategies.
Three methods of
Epigenetic changes typically occur as one of three major events: X chromosome inactivation, parent of origin effects, or imprinting, and environmental effects.
He continued that changes can occur to both the DNA or the proteins around which the DNA is wound. Additions to DNA are commonly present in the form of methylations, or the addition of a CH3 group.
“Methylation additions change the way DNA is read by the machinery of the cell,” he added, noting that this variation turns genes on or off.
Changes that occur in histones are much more complicated and less understood because the type of groups added to histones varies greatly.
Well known epigenetics
“Most people know that females have two X chromosomes and one of those is randomly inactivated,” said Threadgill. “That inactivation occurs through an epigenetic mechanism.”
Parent of origin effects are also a commonly seen epigenetic variation.
“There are a number of human and agriculture species diseases where phenotypes are only manifested depending on which parent you inherit an allele from,” he explained. “These come about through epigenetic modification or DNA imprinting, such that an allele inherited from the father is different from the allele inherited from the mother.”
Parent of origin effects show a different phenotype, depending on if the gene was inherited from the maternal or paternal chromosome. In humans, for example, a particular mutation is expressed as Prader-Willi syndrome if inherited from the paternal chromosome, but the same mutation, if inherited from the maternal genetics, is expressed as Angelman syndrome.
Influence of the
Perhaps more interestingly, and of increasing focus for biomedical researchers, is the effect that environments can have on the epigenetic landscape of animals.
“This is classical epigenetics – the things you actually do to an organism that will not alter the sequence of DNA, but the types of other molecules added to DNA that will be transmitted from one generation to the next,” Threadgill mentioned. “This type of observation could have a direct impact on a lot of what happens in the beef cattle industry.”
One way to influence the epigenetic landscape of an organism is based on their diet, and he noted that in theory, the phenotype of an animals can be altered based on the concentration of methionine fed to cattle.
Developments made in the last 10 years look at the incidence of methylation related to the concentration of methionine in the diet.
“By supplementing the diet with methyl groups, the cell will add extra methylation events,” said Threadgill. “Alternatively, we can give a methyl-deficient diet and the cell is not able to add all of the epigenetic marks it normally would.”
Currently, targeting specific genes to alter their epigenetic modifications isn’t possible, but Threadgill noted that the technology will likely be developed.
Examples of changes in diet affecting development are present in a wide variety of human populations across the world and have been found to impact the subsequent two generations.
In one example, Threadgill mentioned that ewes overfed during pregnancy showed a pronounced phenotypic change in their offspring, noting that though the next generation was fed properly, they were overweight and showed physical differences.
“This is really a developing field,” Threadgill commented. “It is even more complicated than this. It’s not just the genetics that lead to phenotypes. We have to start thinking how we are handling the animals and how much they are fed and stressed because those factors can have effects that last one or two generations.”
The function of epigenetic markers
Beyond adding additional variation to the genome, epigenetic markers are very useful for the cell and serve to compact large amounts of DNA.
“Every single cell in our bodies or in a cow has six feet of DNA in it. How do we take that six feet and condense it down into a size that is one one-hundredth of a pinhead?” asked David Threadgill, head of the Department of Genetics at North Carolina State University. “It takes an excessive amount of molecular regulation.”
Despite being compact, DNA still must be accessible to cell machinery for replication and development of gene products, so the genetic material is wrapped around proteins called histones.
“Histones allow this very long piece of DNA to be coiled and to be dramatically shrunk in size as far as the amount of space it takes,” he said. “There are some additions that occur to these proteins and the primary sequence itself called epigenetic modifications.”
At the most basic level, epigenetic modifications serve to help the entire DNA molecule present in an organism to fit neatly inside its cells.