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Genome-Wide Dna Methylation and Imprinted Gene Analysis In GENOME-WIDE DNA METHYLATION AND IMPRINTED GENE ANALYSIS IN BABIES CONCEIVED BY ART by LUKE DAVID GOODING B.Sc., The University of British Columbia, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Reproductive and Developmental Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2019 © Luke David Gooding, 2019 The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: Genome-wide DNA methylation and imprinted gene analysis in babies conceived by ART submitted by Luke David Gooding in partial fulfillment of the requirements for the degree of Master of Science in Reproductive and Developmental Sciences Examining Committee: Dr. Paul Yong Supervisor Dr. Patrice Eydoux Supervisory Committee Member Dr. Wan Lam Supervisory Committee Member Dr. Angela Devlin Additional Examiner Additional Supervisory Committee Members: Dr. Dan Rurak Supervisory Committee Member ii Abstract Assisted reproductive technologies (ARTs) are associated with a number of adverse pregnancy, neonatal, and long-term outcomes. One plausible explanation is that ART procedures may be causing alterations in epigenetic mechanisms, including the regulation of imprinted genes, that persist during development. Therefore, I investigated gene expression of the imprinted genes PLAGL1, CDKN1C, KCNQ1OT1, and H19 in cord blood from 24 IVF, 18 ICSI, 9 IUI, and 26 naturally conceived babies as well as genome-wide DNA methylation using Illumina’s EPIC methylation array in cord blood from 10 IVF, 9 ICSI, and 10 naturally conceived babies. All the samples were procured from healthy newborn singletons. No differences in the gene expression of the imprinted genes were observed across conception modes. The genome-wide DNA methylation analysis revealed an overall stability of DNA methylation following ART; however, a small number of CpG sites exhibited hypervariability in the ICSI (47 CpG sites) and the IVF (4 CpG sites) groups. Furthermore, the mCSEA method for detecting DMRs revealed 101 promoter associated DMRs in the ICSI group and 101 promoter associated DMRs in the IVF group. 35 DMRs overlapped between the ICSI and IVF groups, suggesting some regions may be susceptible to DNA methylation alterations following ART. Four imprinted gene DMRs were also found to overlap DMRs between conception modes. Overall this analysis revealed that a small number of genomic regions may be impacted by ART. These regions may be significant as genes associated with neurodevelopmental disorders, intrauterine programming of adult onset obesity, and male infertility were observed to be altered in both the IVF and ICSI groups. Although validation of these regions is required, this analysis provides support for ART impacting DNA methylation that persists to birth in genes related to adverse outcomes and mediating transmission of DNA methylation alterations from infertile parents to babies. iii Lay Summary Assisted reproductive technologies (ART) are associated with a small increase in the risk for adverse outcomes that may have some impacts on the long-term health of individuals born via these technologies. One plausible explanation for this increased risk of adverse outcomes following ART is that ART procedures may be affecting environmentally sensitive mechanisms that regulate genes, called epigenetics. I show that epigenetic mechanisms are mostly unaltered in babies born via ART. However, I found a small number of epigenetic alterations that may be linked to the increased risk of adverse outcomes seen in ART conceived individuals. It is possible that these alterations are caused, at least in part, by the infertility of the parents undergoing the ART procedures. These alterations, however, require validation with other measurement techniques before conclusions can be drawn. There is also the possibility that these alterations have other causes that were not considered in this analysis. iv Preface Research in this thesis was approved by the University of British Columbia Children’s and Women’s Research Ethics Board (certificate number: H06- 03668) and was conducted in Dr. Sai Ma’s laboratory with input from Dr. Sai Ma, Dr. Paul Yong, Dr. Wan Lam, Dr. Patrice Eydoux, and Dr. Dan Rurak. Sample collection and clinical information data base management were performed by Kate Watt, Samuel Schafer, Kenny Louie, Rebecca Vincent, and I. DNA extractions were performed by Kate Watt, Samuel Schafer, Rebecca Vincent, and I. In chapter 2, the design of the analysis was proposed by Rebecca Vincent, Samuel Schafer, and I with input from Dr. Sai Ma. I performed all RNA extractions, cDNA library constructions, and qPCR experiments. I performed data processing, statistical analysis, and production of figures with assistance from Kenny Louie. In chapter 3, the design of the analysis was proposed by Kenny Louie and myself with input from Dr. Sai Ma. I performed the sample preparation and collaborated with the Genome Quebec Innovation Centre for EPIC array data procurement. I researched and employed the analytical pipeline with input from Kenny Louie. v Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ............................................................................................................................... iv Preface .............................................................................................................................................v Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ xi List of Figures .............................................................................................................................. xii List of Abbreviations ................................................................................................................. xiii Acknowledgements .................................................................................................................... xvi Dedication .................................................................................................................................. xvii Chapter 1: INTRODUCTION ......................................................................................................1 1.1 Infertility ......................................................................................................................... 1 1.1.1 Lifestyle factors impacting infertility ......................................................................... 1 1.1.2 Male factor infertility .................................................................................................. 3 1.1.3 Female factor infertility .............................................................................................. 6 1.2 Assisted reproductive technologies................................................................................. 8 1.2.1 Intrauterine insemination ............................................................................................ 9 1.2.2 Ovulation induction .................................................................................................. 10 1.2.3 In vitro fertilization ................................................................................................... 10 1.2.4 Intracytoplasmic sperm injection .............................................................................. 11 1.3 Outcomes: assisted reproductive technologies ............................................................. 12 1.3.1 ART singleton outcomes........................................................................................... 13 1.3.2 Long-term outcomes ................................................................................................. 14 vi 1.4 Causes for poor outcomes in ART conceived babies ................................................... 17 1.4.1 Infertility ................................................................................................................... 17 1.4.2 ART procedures ........................................................................................................ 18 1.4.2.1 Mechanisms by which ART procedures may impact outcomes ....................... 20 1.5 Epigenetics .................................................................................................................... 23 1.5.1 DNA methylation ...................................................................................................... 24 1.5.1.1 Genomic regions regulated by DNA methylation ............................................ 25 1.5.1.2 DNA methyltransferases ................................................................................... 26 1.5.1.3 DNA demethylation .......................................................................................... 27 1.5.1.4 Environmental influences on DNA methylation ............................................... 27 1.5.1.5 DNA methylation and age ................................................................................ 28 1.5.2 Genomic imprinting .................................................................................................
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