Jawdat, Razan S.; (2018) Investigating the role of mitochondria at the preimplantation stages of human embryonic development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mitochondria are the major energy producers in cells in the form of ATP. Proteins required for mitochondrial function are encoded by both mitochondrial (mtDNA) and nuclear DNA (nDNA) necessitating compatibility between the two genomes. Good quality oocytes containing an optimal number of mitochondria and sufficient levels of ATP produce higher quality blastocysts. Recent data suggests an elevated level of mtDNA may be associated with aneuploidy in blastocysts. In this study, preimplantation embryo development was investigated in relation to mtDNA template number and aneuploidy. ATP levels were measured in blastocysts and linked to aneuploidy. To investigate possible nDNA/mtDNA mismatch, DNA from couples with repeated miscarriage or repeated implantation failure (RM/RIF) was compared with DNA from couples with no history of infertility but who had preimplantation genetic diagnosis (PGD) for monogenic disorders. DNA from both groups was genotyped using SNP arrays. Sequencing of the mitochondrial genome and a set of 53 nuclear-encoded genes important in mitochondrial function was also performed. Further sequencing of the selected nuclear genes in embryos from the PGD group was used to identify variants in the nuclear and mitochondrial genomes associated with poor embryo development. Our data showed that arrested embryos that were euploid had more mtDNA than arrested embryos that were aneuploid. Aneuploidy in blastocysts resulted in variability in ATP levels. When aneuploidy was present in more than ten chromosomes, ATP was almost undetectable. From the sequencing analysis, significantly more couples with RM/RIF (5/12) had partners from the same mtDNA haplogroup compared with the PGD group of couples (1/11). Yet, SNP data analysed by identity by state (IBS) showed no significant differences between partners in couples based on their nDNA even when the HLA region was considered separately. Within the PGD group, the presence of the T haplogroup in the male partner was associated with a smaller percentage of embryos developing to blastocysts. Analysis of embryos from these couples suggested a link with SNPs in nuclear genes (specifically COQ9 and PPARGC1a) encoding mitochondrial proteins which may contribute to poor embryo development due to a disturbance in the electron transport chain or mitochondrial biogenesis respectively. Determining the mitochondrial haplogroups of both parents is a useful tool to investigate potential mismatch between the nuclear and mitochondrial genomes in embryos which may influence their development.

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