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Genetics and Genomics of Female Reproduction
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Genetics and Genomics of Female Reproduction

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 15 August 2024 | Viewed by 7558

Special Issue Editors

Dr. David Keefe

E-Mail Website
Guest Editor
Department of OB-GYN, Grossman School of Medicine, New York University, 550 First Avenue NBV 9N1-F, New York, NY 10016, USA
Interests: oocytes; embryos; reproductive aging; telomeres; transposable elements; aneuploidy
Dr. Ashley Wiltshire

E-Mail Website
Guest Editor
Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
Interests: oocyte cryopreservation; infertility

Special Issue Information

Dear Colleagues,

Infertility afflicts one in ten women and increases in frequency as women age. Advances in genetics and genomics have made remarkable strides in clarifying the underpinnings of many cases of female infertility. Germline mutations disrupting oocyte and embryo development explain some causes of ovarian dysfunction. The exceptional genetic diversity found in early mammalian development, which results from meiotic recombination, and meiotic as well as mitotic non-disjunction, frequently produces embryo lethal combinations. A plethora of breakthrough technologies in single-cell genomic analysis now enable detection of viable among the more numerous nonviable embryos. Genomics is also shedding new light on uterine pathology, including recognition of an extraordinarily diverse microbiome whose alteration can disrupt embryo implantation. The placenta, so central to mammalian reproduction, is also yielding new insights on human reproduction. Technological breakthroughs in the genetics and genomics of female reproductive function are paving the way not only for novel molecular genetic diagnostics, but also for treatment. Still fraught with ethical and technological challenges, early research on germ line gene engineering is beginning to show promise.

This Special Issue aims to provide a snapshot of some of the most cutting-edge research on the genetics and genomics of female reproduction, with a focus on translational efforts. These contributions illustrate the “awesome power of genetics” when applied to human disease. Progress in this field has emerged from contributions by experts in diverse fields of expertise, who employ a wide array of model systems, including animals, tissue culture and clinical specimens, and cutting-edge technologies. Accordingly, our review reflects the remarkable convergence of expertise from a wide array of specialists. This issue includes both original research papers and critical reviews in order to provide an update which is both comprehensive and current.

Dr. David Keefe
Dr. Ashley Wiltshire
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • female infertility
  • genetics
  • genomics
  • oocytes
  • embryos
  • aneuploidy
  • mitochondrial DNA

Published Papers (6 papers)

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Research

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18 pages, 3434 KiB  
Article
Dynamics of Mitochondrial DNA Copy Number and Membrane Potential in Mouse Pre-Implantation Embryos: Responses to Diverse Types of Oxidative Stress
by Yasmyn E. Winstanley, Jun Liu, Deepak Adhikari, Macarena B. Gonzalez, Darryl L. Russell, John Carroll and Rebecca L. Robker
Genes 2024, 15(3), 367; https://doi.org/10.3390/genes15030367 - 16 Mar 2024
Viewed by 789
Abstract
Mitochondria undergo a myriad of changes during pre-implantation embryo development, including shifts in activity levels and mitochondrial DNA (mtDNA) replication. However, how these distinct aspects of mitochondrial function are linked and their responsiveness to diverse stressors is not well understood. Here, we show [...] Read more.
Mitochondria undergo a myriad of changes during pre-implantation embryo development, including shifts in activity levels and mitochondrial DNA (mtDNA) replication. However, how these distinct aspects of mitochondrial function are linked and their responsiveness to diverse stressors is not well understood. Here, we show that mtDNA content increased between 8-cell embryos and the blastocyst stage, with similar copy numbers per cell in the inner cell mass (ICM) and trophectoderm (TE). In contrast, mitochondrial membrane potential (MMP) was higher in TE than ICM. Culture in ambient oxygen (20% O2) altered both aspects of mitochondrial function: the mtDNA copy number was upregulated in ICM, while MMP was diminished in TE. Embryos cultured in 20% O2 also exhibited delayed development kinetics, impaired implantation, and reduced mtDNA levels in E18 fetal liver. A model of oocyte mitochondrial stress using rotenone showed only a modest effect on on-time development and did not alter the mtDNA copy number in ICM; however, following embryo transfer, mtDNA was higher in the fetal heart. Lastly, endogenous mitochondrial dysfunction, induced by maternal age and obesity, altered the blastocyst mtDNA copy number, but not within the ICM. These results demonstrate that mitochondrial activity and mtDNA content exhibit cell-specific changes and are differentially responsive to diverse types of oxidative stress during pre-implantation embryogenesis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
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14 pages, 2711 KiB  
Article
A Circular RNA Derived from the Pumilio 1 Gene Could Regulate PTEN in Human Cumulus Cells
by Angela Caponnetto, Carmen Ferrara, Anna Fazzio, Noemi Agosta, Marianna Scribano, Maria Elena Vento, Placido Borzì, Cristina Barbagallo, Michele Stella, Marco Ragusa, Paolo Scollo, Davide Barbagallo, Michele Purrello, Cinzia Di Pietro and Rosalia Battaglia
Genes 2024, 15(1), 124; https://doi.org/10.3390/genes15010124 - 19 Jan 2024
Viewed by 881
Abstract
CircRNAs are a class of non-coding RNAs able to regulate gene expression at multiple levels. Their involvement in physiological processes, as well as their altered regulation in different human diseases, both tumoral and non-tumoral, is well documented. However, little is known about their [...] Read more.
CircRNAs are a class of non-coding RNAs able to regulate gene expression at multiple levels. Their involvement in physiological processes, as well as their altered regulation in different human diseases, both tumoral and non-tumoral, is well documented. However, little is known about their involvement in female reproduction. This study aims to identify circRNAs potentially involved in reproductive women’s health. Candidate circRNAs expressed in ovary and sponging miRNAs, already known to be expressed in the ovary, were selected by a computational approach. Using real time PCR, we verified their expression and identified circPUM1 as the most interesting candidate circRNA for further analyses. We assessed the expression of circPUM1 and its linear counterpart in all the follicle compartments and, using a computational and experimental approach, identified circPUM1 direct and indirect targets, miRNAs and mRNAs, respectively, in cumulus cells. We found that both circPUM1 and its mRNA host gene are co-expressed in all the follicle compartments and proposed circPUM1 as a potential regulator of PTEN, finding a strong positive correlation between circPUM1 and PTEN mRNA. These results suggest a possible regulation of PTEN by circPUM1 in cumulus cells and point out the important role of circRNA inside the pathways related to follicle growth and oocyte maturation. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
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10 pages, 264 KiB  
Article
Genetic Variants of Gonadotropins and Their Receptors Could Influence Controlled Ovarian Stimulation: IVF Data from a Prospective Multicenter Study
by Carlo Alviggi, Salvatore Longobardi, Enrico Papaleo, Daniele Santi, Simona Alfano, Valeria Stella Vanni, Maria Rosaria Campitiello, Pasquale De Rosa, Ida Strina, Ilpo Huhtaniemi, Juha-Pekka Pursiheimo, Thomas D’Hooghe, Peter Humaidan and Alessandro Conforti
Genes 2023, 14(6), 1269; https://doi.org/10.3390/genes14061269 - 15 Jun 2023
Cited by 1 | Viewed by 1379
Abstract
Background: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in [...] Read more.
Background: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in women undergoing ART. Methods: A total of 94 normogonadotropic patients from three public ART units were enrolled. Patients underwent a gonadotropin releasing hormone (GnRH) long down-regulation protocol with a starting dose of 150 IU of recombinant follicular stimulating hormone (FSH) daily. Eight polymorphisms were genotyped. Results: A total of 94 women (mean age 30.71 ± 2.61) were recruited. Fewer fertilized and mature oocytes were retrieved in homozygous carriers of luteinizing hormone/choriogonadotropin receptor (LHCGR) 291 (T/T) than in heterozygous C/T carriers (p = 0.035 and p = 0.05, respectively). In FSH receptor (FSHR) rs6165 and FSHR rs6166 carriers, the ratio between total gonadotropin consumption and number of oocytes retrieved differed significantly among three genotypes (p = 0.050), and the ratio was lower in homozygous A/A carriers than in homozygous G/G and heterozygous carriers. Women who co-expressed allele G in FSHR-29 rs1394205 and FSHR rs6166 and allele C LHCGR 291 rs12470652 are characterized by an increased ratio between total FSH dosage and number of oocytes collected after ovarian stimulation (risk ratio: 5.44, CI 95%: 3.18–7.71, p < 0.001). Conclusions: Our study demonstrated that specific polymorphisms affect the response to ovarian stimulation. Despite this finding, more robust studies are required to establish the clinical utility of genotype analysis before ovarian stimulation. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
17 pages, 4000 KiB  
Article
Vitrification with Dimethyl Sulfoxide Induces Transcriptomic Alteration of Gene and Transposable Element Expression in Immature Human Oocytes
by Ashley Wiltshire, Renata Schaal, Fang Wang, Tiffany Tsou, Wilson McKerrow and David Keefe
Genes 2023, 14(6), 1232; https://doi.org/10.3390/genes14061232 - 08 Jun 2023
Viewed by 1533
Abstract
Despite substantial advancements in the field of cryobiology, oocyte and embryo cryopreservation still compromise developmental competence. Furthermore, dimethyl sulfoxide (DMSO), one of the most commonly used cryoprotectants, has been found to exert potent effects on the epigenetic landscape of cultured human cells, as [...] Read more.
Despite substantial advancements in the field of cryobiology, oocyte and embryo cryopreservation still compromise developmental competence. Furthermore, dimethyl sulfoxide (DMSO), one of the most commonly used cryoprotectants, has been found to exert potent effects on the epigenetic landscape of cultured human cells, as well as mouse oocytes and embryos. Little is known about its impact on human oocytes. Additionally, few studies investigate the effects of DMSO on transposable elements (TE), the control of which is essential for the maintenance of genomic instability. The objective of this study was to investigate the impact of vitrification with DMSO-containing cryoprotectant on the transcriptome, including on TEs, of human oocytes. Twenty-four oocytes at the GV stage were donated by four healthy women undergoing elective oocyte cryopreservation. Oocytes were paired such that half from each patient were vitrified with DMSO-containing cryoprotectant (Vitrified Cohort), while the other half were snap frozen in phosphate buffer, unexposed to DMSO (Non-Vitrified Cohort). All oocytes underwent RNA sequencing via a method with high fidelity for single cell analysis, and which allows for the analysis of TE expression through Switching Mechanism at the 5′-end of the RNA Transcript sequencing 2 (SMARTseq2), followed by functional enrichment analysis. Of the 27,837 genes identified by SMARTseq2, 7331 (26.3%) were differentially expressed (p < 0.05). There was a significant dysregulation of genes involved in chromatin and histone modification. Mitochondrial function, as well as the Wnt, insulin, mTOR, HIPPO, and MAPK signaling pathways were also altered. The expression of TEs was positively correlated with the expression of PIWIL2, DNMT3A, and DNMT3B, and negatively correlated with age. These findings suggest that the current standard process of oocyte vitrification, involving DMSO-containing cryoprotectant, induces significant transcriptome changes, including those involving TEs. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
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12 pages, 2677 KiB  
Article
The Landscape of Telomere Length and Telomerase in Human Embryos at Blastocyst Stage
by Fang Wang, David H. McCulloh, Kasey Chan, Ashley Wiltshire, Caroline McCaffrey, James A. Grifo and David L. Keefe
Genes 2023, 14(6), 1200; https://doi.org/10.3390/genes14061200 - 30 May 2023
Cited by 1 | Viewed by 1334
Abstract
The telomere length of human blastocysts exceeds that of oocytes and telomerase activity increases after zygotic activation, peaking at the blastocyst stage. Yet, it is unknown whether aneuploid human embryos at the blastocyst stage exhibit a different profile of telomere length, telomerase gene [...] Read more.
The telomere length of human blastocysts exceeds that of oocytes and telomerase activity increases after zygotic activation, peaking at the blastocyst stage. Yet, it is unknown whether aneuploid human embryos at the blastocyst stage exhibit a different profile of telomere length, telomerase gene expression, and telomerase activity compared to euploid embryos. In present study, 154 cryopreserved human blastocysts, donated by consenting patients, were thawed and assayed for telomere length, telomerase gene expression, and telomerase activity using real-time PCR (qPCR) and immunofluorescence (IF) staining. Aneuploid blastocysts showed longer telomeres, higher telomerase reverse transcriptase (TERT) mRNA expression, and lower telomerase activity compared to euploid blastocysts. The TERT protein was found in all tested embryos via IF staining with anti-hTERT antibody, regardless of ploidy status. Moreover, telomere length or telomerase gene expression did not differ in aneuploid blastocysts between chromosomal gain or loss. Our data demonstrate that telomerase is activated and telomeres are maintained in all human blastocyst stage embryos. The robust telomerase gene expression and telomere maintenance, even in aneuploid human blastocysts, may explain why extended in vitro culture alone is insufficient to cull out aneuploid embryos during in vitro fertilization. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
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Review

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14 pages, 1008 KiB  
Review
Human Reproduction and Disturbed Genomic Imprinting
by Thomas Eggermann
Genes 2024, 15(2), 163; https://doi.org/10.3390/genes15020163 - 26 Jan 2024
Viewed by 977
Abstract
Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting [...] Read more.
Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting disorders (ImpDis). These alterations also affect the function of the placenta, which has consequences for the course of the pregnancy. The molecular causes of ImpDis comprise changes at the DNA level and methylation disturbances (imprinting defects/ImpDefs), and there is an increasing number of reports of both pathogenic fetal and maternal DNA variants causing ImpDefs. These ImpDefs can be inherited, but prediction of the pregnancy complications caused is difficult, as they can cause miscarriages, aneuploidies, health issues for the mother and ImpDis in the child. Due to the complexity of imprinting regulation, each pregnancy or patient with suspected altered genomic imprinting requires a specific workup to identify the precise molecular cause and also careful clinical documentation. This review will cover the current knowledge on the molecular causes of aberrant imprinting signatures and illustrate the need to identify this basis as the prerequisite for personalized genetic and reproductive counselling of families. Full article
(This article belongs to the Special Issue Genetics and Genomics of Female Reproduction)
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