Genetic mutations pile up soon after conception

Right after conception, hundreds of tiny mutations begin to accumulate in cells of a developing fetus, a process that continues, but at a much slower rate, well into adulthood, a new study by researchers at Yale and the Mayo Clinic shows. The investigators compared DNA sequences of single neuronal progenitor cells in the same human brain and discovered they were not identical because of an accumulation of mutations after each cell division following fertilization.

Many of these small variations in DNA occur as sex cells are forming in the embryo, meaning they can be incorporated into the genome and passed on to the next generation for good or ill, researchers report Dec. 7 in the journal Science.

“This opens up a larger perspective on human development,” said co-corresponding author Flora Vaccarino, the Harris Professor in the Child Study Center, professor of neuroscience and a member of the Kavli Institute for Neuroscience. “Some of our genome does not come from our parents.”

The findings may help explain causes of neurodevelopmental disorders such as schizophrenia or autism, which are primarily linked to genetic abnormalities but where no single gene inherited by parents has been found to cause a large number of cases. Researches also found early mutations are remarkably similar in their characteristics to those found in cancers, suggesting cancers can occur as a normal byproduct of cell division.

The analysis of tissue shows that hundreds of single mutations of nucleotides — the genetic “letters” that form DNA — occur in each cell before birth and tend to accelerate very early in development, when neuronal progenitors divide to generate neurons of the central nervous system. Vaccarino and colleagues theorize that mutations are the result of oxidative stress caused by formation of blood vessels distributing oxygen throughout the body, including the developing brain. These mutations are then carried throughout the body as migrating cells form different types of tissue. But they also occur during formation of sex cells, meaning the mutations can be inherited.

This insight into development can help explain why one identical twin may have a genetic disorder and the other is healthy, or why some members of a family who carry a disease-causing mutation do not get sick, the authors say.

Alexej Abyzov of the Mayo Clinic is co-corresponding author of the study, which was primarily funded by the National Institute of Mental Health (NIMH).

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