Mice conceived by in vitro fertilization (IVF) in the laboratory have slightly increased rates of DNA errors, or mutations, compared to their naturally conceived offspring, a new study on artificial reproductive technologies suggests.
While the results are not directly applicable to humans, they highlight the importance of understanding how fertility treatments affect an offspring’s DNA. The research was recently published in the journal Genome Research.
“What we’re seeing is a true biological signal, but we can’t make an apples-to-apples comparison to what happens in a clinic. However, the fact that we see this trend in mice warrants additional research to explore this possibility in humans,” said Beth Dumont, a geneticist at The Jackson Laboratory who led the study.
The researchers compared genome sequences of naturally conceived laboratory mice and mice conceived through assisted reproductive technologies, including hormone treatments, IVF and embryo transfer. They found that newborns born through these fertility treatments had about 30% more new single-nucleotide variants, or tiny changes in their DNA sequences.
Nucleotides are the building blocks or “letters” of DNA. Arranged in specific sequences, these letters make up the instructions that cells use to grow and function. Single nucleotide variants are simply genetic differences (or mutations) that involve a change in a single letter of DNA. They can appear when cells copy their DNA.
The mutations observed in the study are unlikely to be harmful. Scientists estimate that less than 2 percent of new mutations that arise in a genome are harmful or have an impact on a person’s phenotype or susceptibility to disease, Dumont said.
The mutations appeared scattered throughout the genome, rather than concentrated in specific genes. The timing of the appearance of these new mutations in early embryos also appeared similar between the fertility-treated and wild-type groups, suggesting that fertility treatment increases the overall likelihood of new DNA changes but does not affect when they occur during development.
“Although we are seeing an increase in the mutation rate, most of these mutations are found throughout the genome and are neutral mutations that do not have an overall effect on the phenotype of the organism,” Dumont said. “Because it’s not a huge jump in mutation rate, the risk of any of these new mutations being harmful is really, really small — almost negligible.”
Even with a 30% increase in new mutations, the absolute number of harmful new mutations per mouse remains low. For every 50 or so mice conceived by IVF, scientists expect about one additional harmful change in DNA compared to natural conception. This is one problematic change out of many possible, as the mouse genome is approximately 2.7 billion DNA letters long. A similar effect is expected if the age of the male parent is increased by about 30 weeks, Dumont explained, since paternal age is the main driver of mutation rates in mammals.
The biological mechanisms underlying these genetic changes are unclear. Further research is needed to study whether the new mutations arise from a specific step in the IVF process or from the combined effects of several steps. One possible factor is the use of ovarian-stimulating hormone treatments, as these hormones prompt eggs to resume meiosis, a stage of cell division that is known to be error-prone. Other aspects of the fertility treatment protocol could also play a role, such as the physical handling of the embryos or the chemical conditions of the lab culture environment, Dumont said.
The study does not show whether the same effect occurs in humans. Fertility processes vary between mice and humans, and both have different reproductive biology. For example, mice do not menstruate. Also, people seeking IVF will likely face environmental factors that may have already affected their genetics.
Nothing in our study speaks directly to the possibility of mutations in human IVF, but there are associations in the literature that suggest that certain steps in IVF can cause genetic changes. This is clearly worth looking into to ensure that patients are as informed as possible.”
Beth Dumont, geneticist, The Jackson Laboratory
Other authors include Laura Blanco-Berdugo and Alexis Garretson of The Jackson Laboratory.
This work was supported by seed funds from The Jackson Laboratory and a Maximizing Investigators’ Research Award from the National Institute of General Medical Sciences (R35 GM133415).
