Closing the circle of reverse genetics in reproductive medicine
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COMMENTARY
Closing the circle of reverse genetics in reproductive medicine David F. Albertini 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Linking genotype to phenotype is the singular charge of genetics. And some of the most foundational principles in contemporary human genetics took their origins within the annals of reproductive medicine. But since staking claim in the 1960s and 1970s, momentum in human genetics on the broader scale it now commands has been sustained in recent decades by the exploitation of experimentally tractable animal models lending themselves to observational and functional studies of spontaneous, induced, or engineered mutations whose outcomes could be defined in rigorous terms. While intact animal and cultured cell or organoid models have retained a central role in linking genotypes to phenotypes, the field of human genetics is selfpowering forward at an incredible pace thanks in large measure to the remarkable technological advances of the past two decades. Fittingly, we have arrived at a place where a human phenotype can be mapped to a particular gene offering an opportunity to elaborate upon function for gene products perhaps never suspected of being involved in a particular process or behavior at the molecular, cellular, or tissue level. Human ARTs has contributed to transforming the scenario outlined above into a platform of discovery for reproductive biology. A case in point has materialized over the past few years regarding a specific member of the super family of tubulin genes, TUBB8. The first signs or phenotypes prompting inquiry had to do with clusters of patients who despite exhibiting normal responses to ovarian stimulation, yielded immature oocytes at first associated with meiotic arrest at the germinal vesicle stage [1]. In some ways, the ground work set by careful observation of seemingly penetrant phenotypes in the embryology lab heightened awareness of these and other unusual phenotypes in pre or post-fertilization outcomes giving at least the suggestion of a quasi-penetrant phenotype in the face of an otherwise “normal” appearing IVF cycle. But mapping of the original defect to the TUBB8 gene, upon
* David F. Albertini [email protected] 1
Bedford Research Foundation, Bedford, MA, USA
further investigation, revealed in fact that a family of mutations were involved that phenotypically demonstrated a spectrum of disorders spanning from the failed resumption of meiosis after ovulation triggering to failure to fertilize or cleave [1, 2]. In fact, the range of disturbances observed in the oocytes of patients identified with various mutations in the TUBB8 gene is striking and will command much future research to understand basic processes at play during these initial and critical stages of human development [3]. Recently, in the pages of JARG, the work of Zhao and colleagues not only extended the analysis of the TUBB8 gene products in human oocytes but provided an elegant example of how to close the circle in reproductive genetics when such a ro
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