Strategies to Identify Genetic Variants Causing Infertility

Ding, Xinbao; Schimenti, John C.

doi:10.1016/j.molmed.2020.12.008

Cited by 13 publications

(7 citation statements)

References 117 publications

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“…Scalability is also important for screening small molecule libraries for chemicals that may further improve differentiation, or libraries of drugs or compounds in the environment that may impair or negatively impact germ cell development. Considering that genetic causes underlie ∼50% of human infertility 1 , parallelized screening of genetic variants, particularly rare or minor alleles that are classified as variants of uncertain significance (VUS), for impacts on IVG. Functionally interpreting the VUS within genes that essential for gametogenesis is important for genetic counseling, clinical applications, and potentially genome editing to enable people with identified genetic causes of infertility to produce viable gametes in vitro or in vivo 1,42,43 .…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, gametogenesis is a complex and long process that is initiated by the specification of primordial germ cells (PGCs), the precursors of oocytes and sperm. Unraveling the mechanisms of PGC development is crucial for understanding key processes such as sexually dimorphic epigenetic inheritance and the bases of infertility, a relatively common health condition impacting ∼15% of all couples 1 . In mammals, PGCs specified in the embryonic epiblast respond to extrinsic and intrinsic signaling pathways including bone morphogenetic protein (BMP) and WNT signaling.…”

Section: Introductionmentioning

confidence: 99%

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Scalable and Efficient Generation of Mouse Primordial Germ Cell-like Cells

Ding,

Li,

Gao

et al. 2024

Preprint

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Primordial germ cells (PGCs) are the founder cells of the germline. The ability to generate PGC-like cells (PGCLCs) from pluripotent stem cells has advanced our knowledge of gametogenesis and holds promise for developing infertility treatments. However, generating an ample supply of PGCLCs for demanding applications such as high-throughput genetic screens has been a limitation. Here, we demonstrated that simultaneous overexpressing 4 transcriptional factors - Nanog and three PGC master regulators Prdm1, Prdm14 and Tfap2c - in suspended mouse epiblast like cells (EpiLCs) and formative embryonic stem cells (ESCs) results in efficient and cost-effective production of PGCLCs. The overexpression of Nanog enhances the PGC regulatory network and suppresses differentiation of somatic lineages, enabling a significant improvement in the efficiency of PGCLC production. Transcriptomic analysis reveals that differentiated PGCLCs exhibit similarities to in vivo PGCs and are more advanced compared to cytokine-induced PGCLCs. These differentiated PGCLCs could be sustained over prolonged periods of culture and could differentiate into spermatogonia-like cells in vitro. Importantly, the ability to produce PGCLCs at scale, without using costly cytokines, enables biochemical and functional genomic screens to dissect mechanisms of germ cell development and infertility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scalable and Efficient Generation of Mouse Primordial Germ Cell-like Cells

Ding,

Li,

Gao

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Parental genetic assessment mainly includes karyotyping, Y chromosomal micro-deletion testing and CFTR gene mutation identification (31). Karyotyping is the visualisation of prepared chromosomes under a light microscope to detect the numerical and structural alterations.…”

Section: Investigationsmentioning

confidence: 99%

Genetics of fertility: Time to explore

Raguraman

2022

Jaffna Med. J.

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Disorders in human Genetics impact their reproductive potential in several ways such as fertility, retaining fertility and fertility treatment outcomes. However, alterations in genes might be harmless or can bring about detrimental outcomes. Understanding the impact of genetics on reproduction is essential to have better fertility outcomes. An individualized assessment of a couple to identify the underlying aetiology related to genetic problems along with genetic testing is considered the first step of the solution. Moreover, assisted reproductive technologies (ART) are a possible fertility treatment option to address feasible genetic problems even before the establishment of pregnancy. A pre-ART assessment of a couple with potential genetic problems can be carried out with expanded carrier screening and genetic analysis of the gametes and embryo during the ART procedure to detect abnormalities and select a healthy embryo are play an indispensable role to overcome this puzzle.

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“…Elimination of these genes in the mother can lead to loss of fertility. It is likely that many additional factors are responsible for the loss of female fertility in humans, although few have been identified 5 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Whole transcriptome screening for novel genes involved in meiosis and fertility in Drosophila melanogaster

Sun,

Defosse,

Boyd

et al. 2024

Sci Rep

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Reproductive success requires the development of viable oocytes and the accurate segregation of chromosomes during meiosis. Failure to segregate chromosomes properly can lead to infertility, miscarriages, or developmental disorders. A variety of factors contribute to accurate chromosome segregation and oocyte development, such as spindle assembly and sister chromatid cohesion. However, many proteins required for meiosis remain unknown. In this study, we aimed to develop a screening pipeline for identifying novel meiotic and fertility genes using the genome of Drosophila melanogaster. To accomplish this goal, genes upregulated within meiotically active tissues were identified. More than 240 genes with no known function were silenced using RNA interference (RNAi) and the effects on meiosis and fertility were assessed. We identified 94 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development but have not been extensively studied in human or model organisms. Understanding the function of these genes will be an important step towards the understanding of their biological significance during reproduction.

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Strategies to Identify Genetic Variants Causing Infertility

Cited by 13 publications

References 117 publications

Scalable and Efficient Generation of Mouse Primordial Germ Cell-like Cells

Scalable and Efficient Generation of Mouse Primordial Germ Cell-like Cells

Genetics of fertility: Time to explore

Whole transcriptome screening for novel genes involved in meiosis and fertility in Drosophila melanogaster

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