Researchers from the universities of Calgary and Cambridge, UK, have discovered that a mutation in a gene necessary for the metabolism of folic acid not only impacts immediate offspring but can also have detrimental health effects, such as spina bifida and heart abnormalities, on subsequent generations.
The animal study, published this week in the journal Cell, also sheds light on the molecular mechanism of folic acid (also known as folate) during development.
About one in 1,200 children are born with spina bifida. The detrimental effects of folic acid deficiency during pregnancy on development are well known. As a result Canada, and many other countries, have implemented folate fortification programs which require folic acid to be added to cereal products. The aim has been to reduce the incidence of developmental problems, including spina bifida. However, until now, very little was known about how folic acid deficiency caused the diverse range of health problems in offspring.
"Fortification programs have reduced the risk of health effects but not eliminated them completely," says Dr. Jay Cross, with the faculties of medicine and veterinary medicine. "Based on our research, we now believe that it may take more than one generation to eliminate the health problems caused by folate deficiency. In addition, we need to be thinking not just about our own genes and how they impact our health and development, but also those of our descendents."
Cross, also a member of the Alberta Children's Hospital Research Institute, co-authored the study with Dr. Erica Watson from the University of Cambridge. Watson is a University of Calgary alumna and started the work during her PhD studies with Cross before moving to Cambridge.
Researchers from the university used mice for the study because their folic acid metabolism is very similar to humans. This enabled the researchers to explore how the molecular mechanism of folic acid deficiency impacted development, thereby causing developmental problems.
Dr. Roy Gravel, also a co-author of the study and member of the Alberta Childrens' Hospital Research Institute says this study provides a tremendous opportunity to look at the prevention of diseases like spina bifida. "The work began as a study of a gene called Mtrr in mice. The goal was to shed light on how a mutation in Mtrr would affect folate metabolism. The multigeneral effect we observed was completely unexpected," says Gravel.
The Mtrr gene encodes an enzyme that is key to the metabolism of folic acid and, when mutated, causes similar effects to dietary folic acid deficiency. The researchers found that when either the maternal grandmother or the maternal grandfather had this Mtrr mutation, their genetically normal grandchildren were at risk of a wide spectrum of developmental abnormalities, even if the mutated gene was not inherited through to the next generations.
These developmental abnormalities were also seen in the fourth and fifth generations of mice.
Through a series of experiments, researchers discovered that the developmental abnormalities were not passed down genetically. Instead, the defects were the result of "epigenetic" changes, which had been inherited. Epigenetics is a process which turns genes on and off through chemical modifications to DNA without changing the genetic code itself. Epigenetic inheritance refers to the passing along of these epigenetic marks as cells divide during development. It had been previously thought that epigenetic modifications were, for the most part, 'wiped clean' after each generation.
The researchers hypothesize that, for a yet unknown reason, some of these abnormal epigenetic marks caused by the Mtrr mutation escape this normal erasure and are inherited by the next generation. If the abnormal epigenetic marks that regulate genes important for development are inherited, then these generations may develop abnormalities as a result of the wrong genes being turned on or off.
"There have been several recent studies implicating folate in different types of human diseases, not just developmental abnormalities, and so our work provides insights into potential biochemical mechanism but also adds a layer of complexity in thinking about transgenerational effects of folate," says Cross.
"This was a very complex study and initially controversial for some. As a result, we could not have accomplished this work without key collaborations both here in Calgary and Cambridge."
The research for this study was supported by grants from the Canadian Institutes of Health Research and Alberta Innovates-Health Solutions.
Media ContactGloria Visser-Niven
For more information, visit ucalgary.ca. Stay up to date with University of Calgary news headlines on Twitter @UCalgary and in our media centre at ucalgary.ca/news/media.
Gloria Visser-Niven | EurekAlert!
Another reason to exercise: Burning bone fat -- a key to better bone health
19.05.2017 | University of North Carolina Health Care
Disrupted fat breakdown in the brain makes mice dumb
19.05.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...
For the first time, scientists have succeeded in studying the strength of hydrogen bonds in a single molecule using an atomic force microscope. Researchers from the University of Basel’s Swiss Nanoscience Institute network have reported the results in the journal Science Advances.
Hydrogen is the most common element in the universe and is an integral part of almost all organic compounds. Molecules and sections of macromolecules are...
22.05.2017 | Event News
17.05.2017 | Event News
16.05.2017 | Event News
22.05.2017 | Materials Sciences
22.05.2017 | Life Sciences
22.05.2017 | Physics and Astronomy