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| Chromosomal Variations Affect Nearly All Human Embryos |
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| SciMed - Genetics & Genome | |||
| TS-Si News Service | |||
| Thursday, 02 July 2009 08:00 | |||
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Amsterdam, The Netherlands. Scientists have shown a high rate of chromosomal abnormalities following conception that may explain comparatively low fertility rates in humans. Researchers showed for the first time that such abnormalities are present in more than 90% of embryos, even those produced by young, fertile couples, often lost through miscarriage. Genetic variations are expected among humans: animals subject to evolutionary pressures and quality control issues that affect manufacture. Specific variations can be overt, traceable to genetic combinations or interrupted developmental processes, while others result from subtle interactions across the genome. Many (if not most) variations are benign, but others result in debilitating diseases. Some variant birth conditions are not diseases but physical anomalies that depart from expected norms. While not life threatening (at least in the short term), they can pose significant challenges for emotional adjustment or require hormonal/surgical correction. Embryos with chromosomal abnormalities generally do not survive, resulting in a miscarriage early in pregnancy. [N1] As many as 75 percent of first trimester miscarriages are caused by chromosomal issues, often before a woman even knows she is pregnant. However, some chromosomal abnormalities get through, occurring in about 1 in 150 live births, [N2,3] generally caused by by errors in the number or structure of chromosomes during development of the egg or sperm cell. At most, 30% of human conceptions result in a live birth, while more than 50% of spontaneous abortions carry chromosomal aberrations. An emerging consensus views the high rate of chromosomal abnormalities as almost certainly responsible for the low fecundity of humans compared with other mammals. Human genome studies have stimulated new investigations that go beyond a previous focus on genetic combinations and better account all of the human DNA relevant to reporoduction. When combined with data from studies of in vitro fertilization (IVF), scientists can build a more complete picture of the development process from gamete (egg or sperm) formation through birth and beyond. Fertility experts collected the new observations during studies of preimplantation genetic screening (PGS). Trasirionally, a single cell would be removed from the early embryo for genetic testing, since it was hypothesised that the selection of chromosomally normal embryos for uterine transfer would increase the live birth rate and decrease the spontaneous abortion rate per embryo transferred. Such embryos were deemed the most representative of normal human embryogenesis, the process that begins once an egg has been fertilised. The IVF embryos are subjected to PGS in an attempt to select the best embryo for transfer. In vitro culture conditions are known to have only a limited influence on the rate of chromosomal imbalances in IVF/ICSI embryos. [N4] However, the research shows that the selection process does nothing to improve pregnancy and live birth rates. In fact, it can lead to potentially viable embryos being discarded. If one or both parents have a known genetic abnormality, PGS is used to identify embryos with the abnormality and avoid implantation. Evelyne Vanneste is a PhD student in the Centre for Human Genetics and the University Fertility Center at Katholieke Universiteit Leuven (Belgium). Vanneste and her team studied each cell from 23 three or four day-old IVF embryos from young fertile couples (less than 35 years old) who had asked for PGS. In this case, there was an X-linked disorder or microdeletion (loss of a tiny piece of a chromosome) that can cause such disorders as neurofibromatosis type 1 (a cancer predisposition syndrome). The new studies were conducted using a set of technologies that detect chromosomal aberrations in the whole genome (all human chromosomes) of a single cell. The previous technique [N5] could only analyse ten of the approximately 32,000 genetic regions at the same time. The team screened embryonic cells at a much higher resolution and identified more chromosomal abnormalities. Ms. Vanneste says that "Until now, the majority of studies analysing the genetic composition of human embryos used low resolution techniques on embryos derived from couples with fertility problems who are at risk for embryonic aneuploidy, an aberrant number of chromosomes, such as three copies of chromosome 21 that results in Down's syndrome. Therefore, little was known about the frequency and type of chromosomal imbalances in embryos from normal, fertile women". "Our new technique has enabled us to show that chromosomal abnormalities are far more common and complex than previously anticipated, even in embryos from young, normal fertile couples. This leads us to believe that such abnormalities must be present in all human IVF-ICSI embryos." Vanneste reported her team's findings to the 25th annual conference of the European Society of Human Reproduction and Embryology. Her report extends the work done in her previous papers that led to the current study. [C1,2] The scientists say their work has important implications for PGS in fertility treatment, routinely used in many fertility centers for couples who encounter problems with conception. This is a particular concern for patients of advanced maternal age, have experienced repeated implantation failures, miscarriages, or severe male fertility problems. "Although PGS is promoted as a way of increasing the chances of a successful pregnancy," said Ms Vanneste, "there has never been any significant evidence that it does, in fact, increase live birth rates after IVF. Our findings have shown that almost every cell of a human embryo carries a different genetic composition; consequently, the one cell that is analysed genetically is not representative of the rest of the embryo." Vanneste says that "If the tested cell is genetically abnormal, the embryo will not be transferred. But the rest of the embryo might be normal and develop into a healthy person. Therefore, the use of PGS means that potentially viable embryos will be discarded. The prevalent chromosomal instability in all early human IVF embryos explains the failure of PGS to improve the live birth rate per embryo transferred. "I think that we have made a crucial breakthrough that will change the way we do preimplantation genetic diagnosis and PGS and help to advance our ability to improve human fertility," said Ms Vanneste. The data collected as a byproduct on in vitro fertilization activities also contribute to an widening baseline on which to base more detailed analysis of variant birth conditions. Notes[N1] American College of Obstetricians and Gynecologists (ACOG). Your Pregnancy and Birth, 4th Edition. ACOG, Washington, DC, 2005.
[N2] American College of Obstetricians and Gynecologists (ACOG). Prenatal Diagnosis of Fetal Chromosomal Abnormalities. ACOG Practice Bulletin, volume 27, May 2001. [N3] Carey, J.C. Chromosomal Disorders, in Rudolph, C.D, and Rudolph, A.M. (eds.), Rudolph's Pediatrics, 21st Edition, New York, McGraw-Hill Medical Publishing Division, 2003, pages 731-741. [N4] Intracytoplasmic Sperm Injection (ICSI) of eggs. [N5] Fluorescent In Situ Hybridisation (FISH). Citations[C1] Chromosome instability is common in human cleavage-stage embryos. Evelyne Vanneste, Thierry Voet, Cédric Le Caignec, Michèle Ampe, Peter Konings, Cindy Melotte, Sophie Debrock, Mustapha Amyere, Miikka Vikkula, Frans Schuit, Jean-Pierre Fryns, Geert Verbeke, Thomas D'Hooghe, Yves Moreau and Joris R Vermeesch. Nature Medicine 15: 577-583 (2009). doi: 10.1038/nm.1924.
Abstract Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders. [C2] Preimplantation genetic screening for aneuploidy of embryos after in vitro fertilization in women aged at least 35 years: a prospective randomized trial. Sophie Debrock, Cindy Melotte, Carl Spiessens, Karen Peeraer, Evelyne Vanneste, Luc Meeuwis, Christel Meuleman, Jean-Pierre Frijns, Joris R. Vermeesch and Thomas M. D'Hooghe. Fertility and Sterility 2009. Epub ahead of print. doi: 10.1016/j.fertnstert.2008.10.072 Abstract Objective. To test the hypothesis that patients with advanced maternal age (AMA) have a higher implantation rate (IR) after embryo transfer of embryos with a normal chromosomal pattern for the chromosomes studied with preimplantation genetic screening (PGS) compared with patients who had an embryo transfer without PGS. Design. Prospective randomized controlled trial (RCT). Setting. Academic tertiary setting. Patient(s). Patients with AMA (≥35 years). Intervention(s). In an RCT, the clinical IR per embryo transferred was compared after embryo transfer on day 5 or 6 between the PGS group (analysis of chromosomes 13, 16, 18, 21, 22, X, and Y) and the Control group without PGS. Main Outcome Measure(s). No differences were observed between the PGS group and the Control group for the clinical IR (15.1%; 14.9%; rate ratio 1.01; exact confidence interval [CI], 0.25–5.27), the ongoing IR (at 12 weeks) (9.4%; 14.9%), and the live born rate per embryo transferred (9.4%; 14.9%; rate ratio 0.63; exact CI, 0.08–3.37). Fewer embryos were transferred in the PGS group (1.6 ± 0.6) than in the Control group (2.0 ± 0.6). A normal diploid status was observed in 30.3% of the embryos screened by PGS. Conclusion(s). In this RCT, the results did not confirm the hypothesis that PGS results in improved reproductive outcome in patients with AMA. Key Words: Preimplantation genetic screening, in vitro fertilization, advanced maternal age, RCT, embryo quality.
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