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Genetic mechanisms of human ovary development and function: A life course approach

McGlacken-Byrne, Sinéad M.; (2023) Genetic mechanisms of human ovary development and function: A life course approach. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Adult ovary function requires appropriate gonad development, folliculogenesis, and oogenesis, which all begin in fetal life. Genetic mechanisms underlying these processes are interrelated and, when disrupted, result in primary ovarian insufficiency (POI). POI is early-onset in 10% (EO-POI), presenting with primary amenorrhoea or pubertal failure. Clinically, a genetic cause is currently seldom sought. Developing new treatments requires improved molecular insight on an individual basis. Here, several complementary studies are presented with impact for understanding ovarian function across the lifecourse. Firstly, a bulk RNAseq time-series transcriptomic analysis of developing human ovary, testes, and control samples (n=47, four stages between 7/8 and 15/16 weeks post conception) was combined with single-nuclei RNA sequencing (snRNAseq) of two 46,XX ovaries. The fetal ovary was transcriptomically distinct from testis and enriched for specific subsets of nuclear receptors, transcription factors, and meiotic genes. New candidate genes (e.g. meiotic pathways) and novel regulatory networks (e.g. neuroendocrine signaling) were identified. Secondly, X chromosome gene expression was examined. Enrichment of X chromosome genes was seen, particularly those escaping X-inactivation. snRNAseq analysis, including two 45,X ovaries, suggested mechanisms of ovarian dysfunction in Turner Syndrome beyond X chromosome asynapsis: dysregulated proteostasis, mitochondrial insufficiency, and abnormal methylation. Thirdly, exome sequencing of women with EO-POI (n=149) established a molecular aetiology in 29.7% with sporadic POI and 58.8% of kindred with familial POI. A further 30.5% women had a potential genetic aetiology identified. POI was heterogeneous genetically, with pathogenic variants in 73 genes identified and frequent polygenicity. The DNA repair gene, ZSWIM7, and RNA helicase, YTHDC2, were studied in detail and identified as novel causes of POI. Taken together, this work demonstrates a remarkably complex genetic landscape of fetal ovary development and ovarian insufficiency in humans. It highlights the value of integrating genetic analysis in a clinical context with transcriptomic data and suggests directions for future work.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genetic mechanisms of human ovary development and function: A life course approach
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10167786
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