Errors in chromosome segregation during oogenesis and early embryogenesis

Errors in chromosome segregation occurring during human oogenesis and early embryogenesis are very common. Meiotic chromosome development during oogenesis is subdivided into three distinct phases. The crucial events, including meiotic chromosome pairing and recombination, take place from around 11 weeks until birth. Oogenesis is then arrested until ovulation, when the first meiotic division takes place, with the second meiotic division not completed until after fertilization. It is generally accepted that most aneuploid fetal conditions, such as trisomy 21 Down syndrome, are due to maternal chromosome segregation errors. The underlying reasons are not yet fully understood. It is also clear that superimposed on the maternal meiotic chromosome segregation errors, there are a large number of mitotic errors taking place post-zygotically during the first few cell divisions in the embryo. In this chapter, we summarise current knowledge of errors in chromosome segregation during oogenesis and early embryogenesis, with special reference to the clinical implications for successful assisted reproduction

What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate

Preimplantation genetic screening is being scrutinized, as recent randomized clinical trials failed to observe the expected significant increase in live birth rates following fluorescence in situ hybridization (FISH)-based screening. Although these randomized clinical trials are criticized on their design, skills or premature stop, it is generally believed that well-designed and well-executed randomized clinical trials would resolve the debate about the potential benefit of preimplantation genetic screening. Since FISH can analyze only a limited number of chromosomal loci, some of the embryos transferred might be diagnosed as ‘normal’ but in fact be aneuploid for one or more chromosomes not tested. Hence, genome-wide array comparative genome hybridization screening enabling aneuploidy detection of all chromosomes was thought to be a first step toward a better design. We recently showed array screening indeed enables accurate determination of the copy number state of all chromosomes in a single cell. Surprisingly, however, this genome-wide array screening revealed a much higher frequency and complexity of chromosomal aberrations in early embryos than anticipated, with imbalances in a staggering 90% of all embryos. The mitotic error rate in cleavage stage embryos was proven to be higher than the meiotic aneuploidy rate and as a consequence, the genome of a single blastomere is not representative for the genome of the other cells of the embryo. Hence, potentially viable embryos will be discarded upon screening a single blastomere. This observation provides a biological basis for the failure of the randomized clinical trials to increase baby-take-home rates using FISH on cleavage stage embroys

Explanatory pluralism in the medical sciences: theory and practice

Explanatory pluralism is the view that the best form and level of explanation depends on the kind of question one seeks to answer by the explanation, and that in order to answer all questions in the best way possible, we need more than one form and level of explanation. In the first part of this article, we argue that explanatory pluralism holds for the medical sciences, at least in theory. However, in the second part of the article we show that medical research and practice is actually not fully and truly explanatory pluralist yet. Although the literature demonstrates a slowly growing interest in non-reductive explanations in medicine, the dominant approach in medicine is still methodologically reductionist. This implies that non-reductive explanations often do not get the attention they deserve. We argue that the field of medicine could benefit greatly by reconsidering its reductive tendencies and becoming fully and truly explanatory pluralist. Nonetheless, trying to achieve the right balance in the search for and application of reductive and non-reductive explanations will in any case be a difficult exercise

Preimplantation Genetic Diagnosis for Ornithine Transcarbamylase Deficiency by Simultaneous Analysis of Duplex-nested PCR and Fluorescence In Situ Hybridization : A Case Report

Ornithine transcarbamylase (OTC) deficiency is an X-linked co-dominant disorder. A couple, with a previous history of a neonatal death and a therapeutical termination due to OTC deficiency, was referred to our center for preimplantation genetic diagnosis (PGD). The female partner has a nonsense mutation in the exon 9 of the OTC gene (R320X). We carried out nested polymerase chain reaction (PCR) for R320X mutation and fluorescence in situ hybridization (FISH) for aneuploidy screening. Among a total of 11 embryos, two blastomeres per embryo from 9 embryos were biopsied and analyzed by duplex-nested PCR and FISH, and one blastomere per embryo from 2 embryos by only duplex-nested PCR. As a result of PCR and restriction fragment length polymorphism analysis, four embryos were diagnosed as unaffected embryos having the normal OTC gene. Among these embryos, only one embryo was confirmed as euploidy for chromosome X, Y and 18 by FISH analysis. A single normal embryo was transferred to the mother, yielding an unaffected pregnancy and birth of a healthy boy. Based on our results, PCR for mutation loci and FISH for aneuploidy screening with two blastomeres from an embryo could provide higher accuracy for the selection of genetically and chromosomally normal embryos in the PGD for single gene defects

Can Routine Commercial Cord Blood Banking Be Scientifically and Ethically Justified?

Background to the debate: Umbilical cord blood—the blood that remains in the placenta after birth—can be collected and stored frozen for years. A well-accepted use of cord blood is as an alternative to bone marrow as a source of hematopoietic stem cells for allogeneic transplantation to siblings or to unrelated recipients; women can donate cord blood for unrelated recipients to public banks. However, private banks are now open that offer expectant parents the option to pay a fee for the chance to store cord blood for possible future use by that same child (autologous transplantation.

What next for preimplantation genetic screening? A polar body approach!

Screening of human preimplantation embryos for numerical chromosome abnormalities has been conducted mostly at the preimplantation stage using fluorescence in situ hybridization. However, it is clear that preimplantation genetic screening (PGS) as it is currently practiced does not improve live birth rates. Therefore the ESHRE PGS Task Force has decided to start a proof of principle study with the aim of determining whether biopsy of the first and second polar body followed by subsequent analysis of the complete chromosome complement of these polar bodies using an array based technique enables a timely identification of the chromosomal status of an oocyte. If the principle of this approach can be proven, it is obvious that a multicentre randomized controlled trial should then be started to determine the clinical value of this technique. In this way the ESHRE PGS Task Force hopes to redirect preimplantation screening from the blind alley to the main road of assisted reproduction