Do a Mother’s Genes Select her Embryos?
A recent study by McCoy et al. in the journal Science reports on evidence that a genetic mutation in the mother’s genes may contribute to an increased risk of aneuploidy in her embryos and thus reduced fertility.
Human aneuploidy is a condition that exists when the number of chromosomes in the nucleus of a cell is not an exact multiple of 23. A normal human cell will have 23 pairs or 46 chromosomes. Common aneuploidies include monosomy – missing a single chromosome, trisomy – the addition of a single chromosome, and complex aneuploidy where the condition affects two or more chromosomes. Embryonic aneuploidy is usually the result of errors in cell division (meiosis or mitosis). Meiosis occurs in both the maternal and paternal gametes or germ cells (egg and sperm) and is the process by which the gametes prepare for fertilization by reducing their chromosome complement by half (23 chromosomes). In this way, each parent contributes half the chromosomes to the newly formed embryo. Errors in meiosis resulting in meiotic aneuploidy will affect every cell in the embryo. While either parent can be responsible for meiotic aneuploidy, these errors are usually maternally derived, and their incidence increases exponentially as the mother advances over the age of 35 years. Another source of aneuploidy is a result of errors in cell division (mitosis) that occurs after the fertilization, as the embryonic cells begin to replicate and divide. Since only the daughter cells of a mitotic error will be affected, the earlier this occurs in the embryo, the larger the proportion of embryonic cells that will be aneuploid. This often results in embryonic mosaicism, where some of the embryo’s cells have a normal complement of 46 chromosomes, and other cells are aneuploid.
Thus, there are three primary sources of aneuploidy: maternal meiosis, paternal meiosis, and embryonic mitosis with the first being the most common and related to maternal age. McCoy’s group studied over 2000 patients undergoing IVF and tested 20,798 day 3 embryos and 15,388 day 5 embryos. They analyzed the genetic data from the embryos as well as that of both parents. They used this information to identify embryos that were abnormal due to a mitotic error and to determine which parent contributed to this error. They eliminated aneuploid embryos derived from maternal chromosomes, reasoning that these embryos were most likely a result of age-related meiotic errors. Since fewer than 5% of sperm are believed to be aneuploid and because paternal meiotic trisomies were found in less than 1% of analyzed embryos, the authors reasoned that embryos affected by paternal aneuploidies (excluding paternal trisomies) were due to a mitotic error. Thus, they were able to identify all the embryos that were due a mitotic error.
It is known, that regardless of age, some women tend to produce more aneuploid embryos than expected for their age. Is it possible that since the early embryonic mitotic machinery is largely derived from the mother, that abnormalities in chromosome segregation after fertilization (mitotic errors) can be under the influence of genes carried by the mother? Surprisingly, McCoy’s group found a strong association between the mother’s genes and the rate of mitotic errors. The single nucleotide polymorphism (SNP) rs2305957 was associated with this high rate of mitotic aneuploidy and is linked to a gene involved in cell division called Polio-like Kinase 4 (PLK4). PLK4 plays a critical role in centrosome function, a structure that helps organize chromosome separation during cell division. In addition to producing embryos with an increased rate of mitotic errors, women with this mutation also had a lower blastulation rate (produced fewer late-stage [day 5] embryos), presumably due to lethal mitotic errors.
Interestingly, this mutation has a surprisingly high worldwide frequency. One has to wonder how a gene so strongly associated with reduced fertility could have evolved to be so common. The authors note that this mutation is in an area of the genome that underwent positive selection between 400,000 years ago to 100,000 year ago, during the time after our human ancestors split from Neanderthals but before modern human population differentiation. The authors speculate that such a mutation that reduces fertility may have provided a selective advantage by adding to the phenomenon of obscured paternity.
Paternity confusion is a phenomenon that has developed in some non-human primates as well as humans. This hypothesis suggests that obscured paternity due to a women’s concealed ovulation and constant receptivity, is a means to obtain men’s aid in rearing offspring. Thus, this decreased fecundity by augmenting paternity confusion, may have facilitated the large paternal investment in offspring seen in humans. This new finding may both shed some light on some etiologies of infertility as well as allow the development of future diagnostic and/or therapeutic techniques to target and treat these forms of infertility. One has to wonder if treatment and thus selection against this adaptive trait that causes reduced fecundity, may have long-term unintended consequences.
McCoy, Rajiv C., Demko, Zachary, Ryan, Allison, Banjevic, Milena, Hill, Matthew, Sigurjonsson, Styrmir, Rabinowitz, Matthew, Fraser, Hunter B., and Petrov, Dmitri A. Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. Science 348(6231), 235-238. 4-10-2015
Vohr, Samuel H. and Green, Richard E. Aneuploidy and mother’s genes. Science 348(6231), 180-181. 4-10-2015.
Templado, C., Vidal, F., and Estop, A. Aneuploidy in Human Spermatozoa. Cytogenet Genome Res 133(2-4), 91-99. 2011
Delhanty, J. D., Harper, J. C., Ao, A., Handyside, A. H., and Winston, R. M. Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients. Hum.Genet. 99(6), 755-760. 1997.
Nigg, E. A. and Stearns, T. The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries. Nat.Cell Biol. 13(10), 1154-1160. 2011.
Schoroder, Inge. Concealed ovulation and clandestine copulation: a female contribution to human evolution. Ethology and Sociobiology 14(6), 381-389. 1993.
Dr. Nathan Treff of RMANJ had some comments regarding the study referenced in this post. He is the Principal Investigator for the Reproductive Endocrine and Infertility division’s Molecular Genetics Basic Science Research Laboratory and an Assistant Professor of Obstetrics and Gynecology at Robert Wood Johnson Medical School, New Brunswick, N.J. Dr. Treff has developed and led the division’s molecular biology research team towards improving the treatment of infertility. He has unique insights on this area of study and has drafted some observations about the paper:
“Unfortunately, the technology used in this study to determine whether certain embryos were aneuploid or euploid is one of the most inaccurate in the field today. This technology, termed “parental support” and offered by Natera, has failed to demonstrate clinical benefit in many settings. For example, RMA of New York found that success rates were significantly lower than with Comprehensive Chromosome Screening (CCS) performed at the Foundation for Embryonic Competence (FEC) (22% compared to 72% implantation rate, respectively)(1). Unlike CCS technology at FEC, Natera’s methods have not undergone rigorous clinical validation such as a randomized controlled trial to evaluate efficacy(2-4), or a “non-selection” study to determine the negative predictive value(5). While the premise of the study published here is worthy of consideration, it is critical to have an accurate method of measuring aneuploidy prior to asking the question.
Another important limitation of this paper is the lack of identification of a “causative variant.” The authors only found what they believe to be a marker that is linked to an important region of the genome. However, the marker itself has no impact on the function of nearby genes such as PLK4. It is standard in the field to follow up this type of association study with detailed investigation to identify a variant that does actually impact the function of nearby genes (causative variant). This study failed to do so and therefore significantly diminishes the relevance of the results presented.
The FEC has an ongoing study funded through the EMD Serono Grants in Fertility Innovation to identify causative variants which predict the risk of producing an aneuploid conception at a younger age than usual maternal age. The project, titled “PREDICTING REPRODUCTIVE POTENTIAL FROM THE MATERNAL EXOME,” will overcome these and other major limitations of the study published by McCoy’s group. We look forward to sharing preliminary results with you in the near future and to our field in general at the 2015 ASRM annual meeting.”
- Lee JA, Barritt J, Duke M, Sandler B, Mukherjee T, Copperman AB. The progression of PGS: technological advancements and application improves implantation and clinical pregnancy rates by enhancing diagnostic accuracy in identifying the euploid embryo Fertil Steril 2012;98:S106-S7.
- Scott RT, Jr., Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril 2013;100:697-703.
- Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril 2013;100:100-7 e1.
- Schoolcraft WB, Surrey E, Minjarez D, Gustofson RL, Scott RT, Jr., Katz-Jaffe MG. Comprehensive chromosome screening (CCS) with vitrification results in improved clinical outcome in women >35 years: a randomized control trial Fertil Steril 2012;98:S1.
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