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Investigation of Aneuploidy in Preimplantation Embryos by Thalia

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Investigation of Aneuploidy in Preimplantation Embryos by Thalia Investigation of aneuploidy in preimplantation embryos by Thalia Mamas A thesis submitted for the degree of Doctor of Philosophy at University College London October 2012 UCL Centre for PGD Institute for Women’s Health University College London 1 ‘I, Thalia Mamas, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.’ 2 Acknowledgements This thesis could have never been the result of one person alone. During my life as a PhD student the number of people that have supported, helped and stood by me has grown to be very big. They say that the student-supervisor relationship is very important in the outcome of a PhD. I was very lucky to be supervised by Dr Sioban SenGupta, who I whole- heartedly thank for her continuous guidance, support, patience and care that she showed towards me during all these years. Many thanks should also be granted to my second supervisor, Dr Joyce Harper. Because of Joyce we were able to attend so many meeting and conferences, expand our knowledge and form scientific opinions. Also, thanks to Joyce I started working on aCGH. Of course the contribution of Professor Joy Delhanty, direct or indirect, in the management of our group and towards my appreciation on chromosomes, should not be left unmentioned. I have spent nearly 8 years in Chenies Mews as a member of the UCL Centre for PGD and it has become my second home. So many people have come and gone that made my time there definitely unforgettable and I know that many friendships have started, that will never end. First of all Leoni, the only person who has been with me from the very beginning until the very end. My dear friend, companion in laughs and tears, inside and outside UCL. Georgia, my bench neighbour, the partner in singing, dancing and experimenting in the lab. Her support while she was in UCL and even after she left has helped me enormously. The time of the dynamic trio of the old PCR group, consisting of Georgia, Seema and me will never be forgotten. Seema also introduced me to the fascinating aspects of single cell work, made sure that I was always behaving and that the long hours of PCR cases were never boring. Pinar, my favourite of all the MSc students that I had the chance to supervise, and then as a PhD student one more very good bench neighbour. Together with Pinar we learnt how to perform aCGH. Former members of the group, now friends, have also helped enormously all these years. Anna and Anastasia showed me how to perform my first FISH experiments and made my first contact with aneuploidy not to feel very scary. Stavros had the difficult role of trying to introduce me and make me understand aCGH and in the end he managed to succeed. Elpida and Souraya were and still are there for help and guidance with everything I need. Of course, current members of the group, Harita, Roy, Aisha, 3 Amanthi and Razan, continue to make our lab an enjoyable and definitely never boring place to work. Special warm thanks should go to people outside our lab that made this work possible. Thanks to all the doctors, nurses and embryologists at the CRGH, the valuable source of our material. I would like to thank Alpesh for providing the information on the IVF cycle procedure and Karen for being a fantastic link between the CRGH and us. I would also like to thank Dr Tony Gordon and Dr Anthony Brown from BlueGnome for providing the microarrays and their help with interpretation and analysis, Dr Dimitra Dafou and Dr Kate Lawrenson for providing the cell lines and finally everyone from the ground floor lab that allowed us to use their genetic analyser. Finally, I would like to thank Dr Nick Maniatis and Dr Winston Lau for their valuable contribution in the development, analysis and interpretation of the recombination chapter. My friends have always been a great source of support, energy and understanding. People in London and Athens, John, Leyton, Stellou, Sugar, Chrysanthi, Maria, Irene were there when I wanted to forget about experiments and writing and made sure I had fun. I would also like to thank Giannis for his support, help, patience and encouragement through these past difficult months of writing, Finally, I feel enormous gratitude to my family, my father, Leonidas, my mother, Maria and my sister Eva. Without their love and support I would have never been able to start, continue and complete this. My dad is the source of inspiration on what I chose to do, my mom is the only person in the world that will always understand me and try in any way possible to make me feel good and my sister, is the person that I know will always be the first I can rely on for everything. I really want to make them proud. 4 To my father, mother and sister 5 ABSTRACT Aneuploidy is common in human preimplantation embryos. This thesis examines aneuploidy detection using an array platform, aneuploidy in embryos from fertile couples and recombination in gametes through the detection of cross-over events in embryos. The first aim of this project was the optimisation of array comparative genomic hybridisation (aCGH) to examine all chromosomes in single blastomeres and trophectoderm samples from embryos, prior to clinical implementation. Accurate detection of errors was possible on single cells from epithelial cell lines of known chromosomal status. The same cell lines were used to mimic mosaic trophectoderm samples to examine the effect of mosaicism on aCGH. Aneuploidy could be confidently detected when more than 50% of the cells in the sample were abnormal. Aneuploidy studies have been mainly performed on embryos, from couples undergoing preimplantation genetic screening (PGS), which are expected to be highly abnormal. The second aim was to determine the aneuploidy level in embryos from couples undergoing preimplantation genetic diagnosis (PGD) for monogenic disorders. Fluorescence in situ hybridisation (FISH) was used to examine five chromosomes in 86 embryos from 19 couples and all chromosomes were examined in 53 embryos from six couples by aCGH. Diploid mosaic embryos were the most predominant group when FISH analysis was carried out, whereas the majority of embryos were euploid after aCGH. Post-zygotic rather than meiotic errors were more common in embryos from PGD cycles when compared to embryos from PGS cycles. Aneuploidy is known to associate with aberrant recombination. The third aim was to examine meiotic recombination. Polymorphic markers on five chromosomes were used to detect cross-over events in 77 embryos from 10 couples. Female recombination was higher than male. Increasing age had a negative effect on recombination. No significant effect of recombination on morphology and aneuploidy was observed, however euploid embryos had more recombination than aneuploid. 6 Table of contents Acknowledgements.......................................................................................3 Abstract..........................................................................................................6 Table of contents...........................................................................................7 List of figures...............................................................................................12 List of tables................................................................................................14 Abbreviations...............................................................................................16 1 Introduction .......................................................................................... 20 1.1 Aneuploidy ............................................................................................... 21 1.1.1 Cell division – Mitosis and Meiosis ...................................................... 21 1.1.1.1 Recombination. Differences between individuals and chromosomes. ....... 26 1.1.2 Incidence of aneuploidy ...................................................................... 28 1.1.2.1 Cytogenetic and molecular cytogenetic methods to study aneuploidy ....... 28 1.1.2.2 Incidence of aneuploidy in the gametes ..................................................... 28 1.1.2.3 Incidence of aneuploidy in preimplantation embryos ................................. 29 1.1.2.3.1 Preimplantation embryo mosaicism ..................................................... 31 1.1.2.3.2 Mosaicism during different stages of preimplantation embryo development and pregnancy .................................................................................. 32 1.1.3 Origin of aneuploidy ............................................................................ 33 1.1.4 Causes of aneuploidy.......................................................................... 34 1.2 Preimplantation genetic diagnosis and screening ................................ 38 1.2.1 Biopsy ................................................................................................. 38 1.2.1.1 Polar body biopsy ....................................................................................... 38 1.2.1.2 Cleavage stage biopsy ............................................................................... 39 1.2.1.3 Blastocyst biopsy ........................................................................................ 40 1.2.2 Preimplantation genetic diagnosis ....................................................... 40 1.2.2.1 Techniques used in PGD for the detection of monogenic disorders .......... 41 1.2.3 Preimplantation genetic
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