09 Oct Gene Linked to Chromosome Abnormalities Identified
Medical Research: What is the background for this study? What are the main findings?
Dr. McCoy: Aneuploidy—the inheritance of extra or missing chromosomes compared to the typical 46-chromosome set—is extremely common in human embryos. The vast majority of aneuploidies result in preclinical pregnancy loss, often before the pregnancy is even recognized by the mother. This is thought to be the primary reason why only ~30% of all conceptions result in successful live birth.
Many aneuploidies arise during egg formation, with the frequency increasing with maternal age. In addition to meiotic errors, a large proportion of aneuploidies affecting cleavage-stage embryos are mitotic in origin, arising during the initial post-fertilization cell divisions. These initial divisions are controlled by machinery contributed by the mother in the egg (before the embryo’s genome has been activated). While these mitotic errors are frequent in cleavage-stage embryos, we found that they are rare in embryos at day-5 of development (the blastocyst stage), suggesting that embryos and/or cells with extensive mitotic errors do not survive to day 5. We discovered that some women have a greater propensity to produce embryos with mitotic errors than others, and our idea was that maybe differences in the mitotic machinery could help explain this.
Using data from in vitro fertilized embryos screened by our collaborators at Natera, we found that women who have a particular version of a gene called PLK4 tend to produce more aneuploid embryos, regardless of age. This genetic variant is actually very common—more than half of people carry at least one copy—and is present in nearly all populations. PLK4 has a well-known role in ensuring the proper distribution of chromosomes. We also found that patients referred for embryo screening due to previous IVF failure had higher rates of mitotic error, which underscores the clinical importance of this form of whole-chromosome abnormality.
Medical Research: What should clinicians and patients take away from your report?
Dr. McCoy: Our study highlights the fact that aneuploidy is a common feature of human reproduction and early development and demonstrates that aneuploidies are diverse in their etiology. We identified a genetic variant that influences one important pathway leading to aneuploidy formation. Since aneuploidy is the leading cause of pregnancy loss, understanding natural pathways contributing to aneuploidy could help pave the way for future fertility treatments or diagnostics.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. McCoy: The next steps will be biological validation and quantification of the effect. Is PLK4 indeed the gene that is responsible? Can we identify the causal variant driving the association and the functional mechanism by which it acts? We are also working on understanding how this may or may not affect fertility-related traits of immediate clinical interest. For example, we are hypothesizing that the genetic variant might affect the average time that it takes a woman to achieve successful pregnancy with unprotected intercourse. If true, then knowing one’s genotype could have diagnostic value and be useful for family planning.
2015 American Society of Human Genetics Annual Meeting abstract:
R. C. McCoy 1 ; Z. Demko 2 ; A. Ryan 2 ; M. Banjevic 2 ; M. Hill 2 ; S. Sigurjonsson 2 ; M. Rabinowitz 2 ; H. B. Fraser 1 ; D. A. Petrov 1
1) Department of Biology, Stanford University, Stanford, CA; 2) Natera, Inc., San Carlos, CA.
Rajiv McCoy, PhD (2015). Gene Linked to IVF Failure Identified