Genetic Missing Link Could Explain Mystery of Heritability
News Jul 11, 2016
The heritability of certain conditions, such as diabetes and obesity, cannot be attributed to genetic differences alone. To some degree, heritability depends on environmental conditions, such as nutritional insult during early-life development, that affect the genome at the epigenetic level, where gene expression can be enhanced or suppressed depending on the accumulation of chemical changes that affect genes without altering underlying DNA sequences.
While epigenetic changes are of intense interest, such changes in certain parts of the genome have been relatively overlooked. And it turns out that one part of the genome—ribosomal DNA (rDNA)—may acquire epigenetic modifications early in an organism’s life, with life-long consequences. Specifically, a type of epigenetic change called DNA methylation may occur depending on the environment in the womb, affecting an offspring’s attributes, such as birth weight.
This finding emerged from a study led by researchers at Queen Mary University of London (QMUL). It confirms that environmental factors in the in utero environment play a role alongside genetic factors in determining an offspring’s attributes. When offspring are in the womb, what their mothers experience environmentally (for example, diet, stress, and smoking), influences the attributes of offspring when they are adults. This “developmental programming” is understood to be a large contributor to the obesity epidemic seen today.
The QMUL described the rDNA dimension to this kind of epigenetic inheritance in an article (“Early-Life Nutrition Modulates the Epigenetic State of Specific rDNA Genetic Variants in Mice”) that appeared July 7 in the journal Science.
“We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA),” wrote the authors. “This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets.”
The authors added that their work has established rDNA as a genomic target of nutritional insults.
"The fact that genetic variation of rDNA seems to play such a major role suggests that many human genetics studies could be missing a key part of the puzzle,” asserted Vardhman Rakyan, Ph.D., a professor at QMUL and the current study’s lead researcher. “These studies only looked at a single copy part of individuals' genomes and never at rDNA.
“This could be the reason why we've only so far been able to explain a small fraction of the heritability of many health conditions, which makes a lot of sense in the context of metabolic diseases, such as type 2 diabetes.”
The QMUL researchers found that when cells are stressed—for example, when nutrient levels are low—they alter protein production as a survival strategy. In the study’s low-protein mice mothers, the researchers saw that mothers’ offspring had methylated rDNA. This slowed the expression of their rDNA, which could be influencing the function of ribosomes and resulted in smaller offspring, as much as 25% lighter.
"Looking beyond the epigenetic markers, when we looked at the basic genetic sequence of the rDNA, we found an even bigger surprise,” added Professor Rakyan. “Even though all the mice in the study were bred to be genetically identical, we found that the rDNA between the individual mice was not genetically identical, and that even within an individual mouse, different copies of rDNA were genetically distinct. So there is huge variation in rDNA which is also playing a big role in determining the attributes of offspring.”
In any given genome, there are many copies of rDNA, and Professor Rakyan and colleagues found that not all copies of the rDNA were responding epigenetically. In offspring from mothers who were fed on low-protein diets, it was only one form of rDNA—the A variant—that appeared to undergo methylation and affect weight.
This means that the epigenetic response of a given mouse is determined by the genetic variation of the rDNA—those who have more A variant rDNA end up being smaller.
The findings also complement other studies that have found that mice that are put on high-fat diets have offspring who show increased rDNA methylation. This suggests that methylation is a general stress response and may also explain the rise in obesity that is happening across the world.