Conditions experienced in the womb will have life-long impact on health. When conditions are harsh, random differences in gene expression may provide a survival advantage to the embryos. By studying DNA methylation, a mechanism to control gene activity, scientists found out a specific part of DNA methylation was missing among individuals exposed to famine.
The new research was motivated by the observation that people conceived during the Dutch Hunger Winter of 1944-1945 suffer from reduced cardiovascular health in their sixties. This can be attributed to persistent changes in how genes are expressed, through so-called epigenetic modification of the DNA. "We know that a lack of nutrition decreases the likelihood of an embryo to survive. Our new study indicates that surviving famine in the uterus hinged on having a DNA methylation pattern allowing continued growth of the embryo in spite of limited resources. But those same methylation patterns may have adverse health effects much later in life", says Bas Heijmans, epigeneticist at the Leiden University Medical Center.
‘At times of severe famine, DNA methylation pattern in the growing fetus will help the embryo to grow regardless of the limited resources. But, the same methylation pattern will have adverse health effects in the future.’
To understand the interplay between epigenetics and survival of the embryo, the researchers took inspiration from evolutionary biology. In evolution, random genetic variation is filtered by natural selection, resulting in accumulation of variants that best 'fit' the environment. A computer model showed that random epigenetic variation between embryos is inevitable, just like genetic mutation. Some of the random DNA methylation variants may enhance an embryo's chance to survive on low nutrition. As a consequence, those epigenetic variants will become more common in cohorts that were exposed to a famine as embryos. "We have always struggled to explain how early embryos would be able to modify specific epigenetic marks in response to nutrition. It is fascinating that selective survival based on random epigenetic variation fits the data best", says Tobias Uller, evolutionary biologist at Lund University.
Some health effects of the Dutch Famine only show later in life and those exposed during early gestation seem to be most affected. "These findings have often been interpreted as conclusive proof of fetal adaptations in the womb that will lead to adult disease if the adult environment changes for the better. But our findings point to a different mechanism", says L.H. Lumey, MD, epidemiologist at Columbia Mailman School and principal investigator of the Dutch Hunger Winter Families study.