Neil Osterweil

October 09, 2015

BALTIMORE — A genetic variant commonly found in women is strongly associated with chromosomal abnormalities that can lead to the failure of in vitro fertilization (IVF), investigators report.

An analysis of embryos submitted for preimplantation genetic screening showed that the variant in the mother's genome appears to be linked to a gene responsible for abnormal rearrangements of chromosomes that occur during cellular replication, said Rajiv McCoy, PhD, a postdoctoral research fellow at the University of Washington in Seattle.

He presented the results here at the American Society of Human Genetics 2015 Annual Meeting.

These abnormal rearrangements, or mitotic aneuploidies, are common in 3-day-old blastomeres, but are rare in 5-day-old embryos, suggesting that the embryos that carry the aneuploidies do not survive. The presence of the genetic variant could explain why some women have particular difficulty with fertility, Dr McCoy told Medscape Medical News.

The investigators hypothesized that because "the first three embryonic cell divisions are controlled by maternal gene products deposited into the egg before the embryo's genome is actually turned on, or becomes active, variation in these maternal gene products might influence rates of aneuploidy in early embryos," he explained.

In a previous study Dr McCoy was involved in, a close association was shown between the rs2305957 single-nucleotide polymorphism (SNP) and high rates of error during embryonic mitosis (Science. 2015;348:235-238). In addition, it was determined that this SNP is found in high frequency in all women.

SNP Found

In that study, the SNP was traced to a region of chromosome 4 that harbors a candidate causal gene, Polo-like kinase 4 (PLK4), which is known to regulate chromosomal distribution during cellular division.

In their current investigation, Dr McCoy and his colleagues analyzed 46,439 embryos from 6366 embryo cycles submitted by about 2400 women for preimplantation genetic diagnosis.

In addition to finding an association between the SNP and the genotype, they found that aneuploid embryos were more likely to have come from women with a history of IVF failure, which suggests that aneuploidy caused the treatment to fail.

This is fascinating to think about.

"When we look at just the number of embryos that are submitted at day 5 for the different genotypic classes of mothers, we see that mothers with the high-risk allele, with higher rates of aneuploidy in 3-day embryos, submitted fewer embryos for testing at day 5, which supports our idea," said Dr McCoy.

If about half of all women have this genetic variant, as studies suggest, it raises the question of why the SNP has not been selected out during human evolution.

The investigators hypothesize that there might be a survival advantage to live-born children of parents with fertility problems. If, the thinking goes, such parents have only one or two, instead of multiple, children, their genetic and emotional investment in the survivors would be all the greater, and those children would be more likely to live to reproductive age, and thus pass on the otherwise deleterious SNP.

The investigators hope to identify the gene responsible for mitotic aneuploidy in these cases and, ideally, determine the underlying molecular mechanisms.

"This is fascinating to think about," said Chris Gunter, PhD, associate professor of pediatrics at the Emory University School of Medicine in Atlanta.

A lot of the research on the genetics of infertility "has looked at whether there are imbalances in the embryo," she told Medscape Medical News. "This is something in the maternal environment that would contribute to that."

This research was internally supported. Dr McCoy and Dr Gunter have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2015 Annual Meeting: Abstract 200. Presented October 8, 2015.


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