What pregnant women eat during pregnancy could determine the weight of their offspring in adulthood.
The study finds that attributes, such as weight, could be shaped by genetic variation in an unexpected area of the genome.
The discovery, published in Science and co-authored by University of Cambridge and King's College London, could provide the missing link in the conundrum of disease inheritance.
Findings from the research demonstrate that the genetic variation of ribosomal DNA (rDNA) could be guiding how the environment within the womb determines an offspring's attributes. rDNA is the genetic material that forms protein-building ribosomes within the cell.
Prof. Vardhman Rakyan, the lead researcher from Queen Mary University of London, says, "The fact that genetic variation of ribosomal DNA seems to play such a major role suggests that many human genetics studies could be missing a key part of the puzzle. These studies only looked at a single copy part of individuals' genomes and never at ribosomal DNA."
"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," he adds.
Epigenetics and offspring
Environmental factors, such as diet, stress, and smoking, work alongside genetic factors in the in-utero environment to influence the attributes of offspring as adults. It is this developmental programming that could contribute to the increase in obesity.
Epigenetics is a significant contributor to this process. Epigenetics refers to external modifications to DNA that turn genes "on" or "off." These modifications do not change the DNA sequence, but instead, affect how they are expressed.
One such modification involves tagging DNA with chemical compounds called methyl groups. These epigenetic markers determine which genes are or are not expressed.
It has been proposed that in response to a poor in-utero environment, an offspring's epigenetic profile will change.
The team compared how a low-protein diet of 8 percent protein and a normal diet of 20 percent protein affected the offspring of pregnant mice. After weaning on a normal diet, the researchers observed any differences in the offspring's DNA methylation.
Low-protein diet resulted in smaller offspring
Initially, the team found nothing, but after analyzing the ribosomal data in a different way, they found huge epigenetic differences.
"When cells are stressed, for example when nutrient levels are low, they alter protein production as a survival strategy. In our low-protein mice mothers, we saw that their 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 percent lighter," says Prof. Rakyan.
These epigenetic effects occur in a critical timeframe of the offspring's development in-utero, and these effects are permanent through adulthood. A mother's diet while pregnant could have more of an effect on the offspring's epigenetic state and weight than the offspring's diet itself after weaning.
Prof. Rakyan notes that when examining the basic genetic sequence of the rDNA in the genetically identical mice, the rDNA between the individual mice was not genetically identical, and even within an individual mouse, different copies of rDNA were genetically different. These variations in rDNA determine the attributes of the offspring.
There are several copies of rDNA in any given genome. The team found that not all the copies of the rDNA were responding epigenetically. Offspring from those mothers fed on the low-protein diets had only one form of rDNA - the "A-variant" - that seemed to experience methylation and affect weight.
Those mice that had more A-variant rDNA developed into the smallest of all the offspring.
The heritability of type 2 diabetes is estimated to be between 25-80 percent, but genome studies have only accounted for 20 percent. The significant role that genetic variation of rDNA plays could explain some of this missing heritability.
The findings also show that mice provided with a high-fat diet had offspring with increased rDNA methylation. The authors suggest that methylation could be a general stress response and may also explain the rise in obesity worldwide.