Selective survival of embryos under adverse conditions may explain health problems later in life

An international team led by researchers of the Leiden University Medical Center and Lund University in Sweden propose that selection of random epigenetic differences causes particular embryos to survive under adverse conditions in the womb. The embryos that survive may, however, end up with poor health as adults. The scientists report their findings in Cell Reports.

The conditions encountered in the womb can have life-long impact on health. Scientists have previously assumed that this is because embryos respond to adverse conditions by programming their gene expression. Now researchers propose a radically different alternative. Rather than being programmed by the environment, random differences in gene expression may provide some embryos with a survival advantage, in particular when conditions are harsh. By studying DNA methylation, an important mechanism to control gene activity, the researchers found that a specific part of the DNA methylation pattern was missing among famine-exposed individuals.

Growth with limited resources

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.

Computer model

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.