The future of reproductive medicine with an expanding toolkit: completion of the human reference genome

Now is no time to think of what you do not have.

Think of what you can do with what there is.

Ernest Hemingway-The old man and the sea

Faced with the daunting prospect of losing his career-best catch to the attack of sharks, Santiago must decide with how to save what remains of his catch (and likely his life) with what tools are available on his drifting skiff. Not much was onboard, but the narrator here reminds him that rather than thinking about what could have been, he best be resourceful in the moment and draw upon what remains in his grasp.

With the recently published complete human reference genome, the list of things made possible within the purview of the biomedical enterprise has taken an enormous step forward [1]. After years of dealing with surprises like how little of our genome was dedicated to gene expression or why so much “junk DNA” was without purpose, that sketch based upon previous iterations of hominin reference genomes has now been replaced by the full deck and is now available for play. The Telomere-to-Telomere Consortium (T2T) has more than filled in holes. Having a reference genome of the quality and depth provided by this work will most certainly open doors to discovery limited until now by missing data links. Among the challenges overcome in this recent tour de force were details within centromeric DNA now revealing complete genomic and epigenetic profiles for each human chromosome [2] and the exposition of repeat elements with respect to both transcriptional and epigenetic status as efforts continue to illuminate much more than the linearity of our favorite genome [3]. This special issue of Science is well worth a closer look into the findings and multiple implications this advance—availing the entire toolkit as it were—will have on medicine broadly but for reproductive medicine and genetics in particular.

An immediate case in point derives from recent findings on the relationship between circulating levels of anti-Müllerian hormone (AMH) and ovarian physiology. Verdiesen and colleagues [4] take to task all matters of AMH in their meta-analysis of three cohort studies in which the search for genetic variants might be linked to levels of AMH in premenopausal women. Their GWAS study hones in on variants implicated in the control of ovarian follicular development given the central role of AMH as both a biomarker of the ovarian reserve but as well what has long been recognized as a critical determinant during the transition of a pre-antral follicle to antral. As had previously been suggested by others, the present work identified MCM8, a gene whose products have been implicated in the control of DNA replication, as a not insignificant player given the explosive degree of cell proliferation known to occur at the onset of antral follicle growth.

What was novel however was the discovery of SNP variants for three previously unrecognized genes in AMH, TEX41, and CDCA7. Besides the obvious implication for AMH locus, roles inclusive for both DNA replication and apoptosis for the other novel SNPs suggest a linkage consistent again with the most basic dimension of ovarian physiology at least at the level of folliculogenesis. To some, why this work draws attention to the role of apoptosis may not be so obvious. But if functional analyses hold true, it will not be solely the driving force of cell proliferation that meets the demands of follicle growth and differentiation but the tipping point between life and death—apoptosis—that underscores the very basis of selection and designation of which follicles follow the path of atresia. As Arvis and colleagues remind us in this issue, accurate measurements of both AMH and antral follicle count are vital tools in the daily practice of ARTs (Reliability of AMH and AFC measurements and their correlation: a large multicenter study; https://doi.org/10.1007/s10815-022-02449). It will be of great interest to now study the relationship between AMH and ovarian pathophysiology with both the reference genome in hand and important leads like those provided by GWAS studies of this kind.

And more to the subject of programmed cell death as was recently the subject of a commentary in JARG. The paper by Dey and Luciano [5] emphasized that while our mindset has been fixed on classical forms of apoptosis, many variations on the theme of apoptosis have been discovered that are appearing to play key roles in human reproduction at all levels of the hypothalamic-pituitary–gonadal axis. While this paper emphasized the role of apoptosis in granulosa cell survival and differentiation, the fact that many factors influence both the type and context for engaging particular forms of programmed cell death has become a matter of extreme importance. Examples in this issue of JARG include the role of fatty acid metabolism in patients exhibiting diminished ovarian reserve (Decreased fatty acids induced granulosa cell apoptosis in patients with diminished ovarian reserve; https://doi.org/10.1007/s10815-022-02462) and one of the newer cell death mechanisms attracting much attention in reproductive medicine, that of ferroptosis (Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers; https://doi.org/10.1007/s10815-022-02443).

In conclusion, with the new reference genome onboard, and the marriage of this knowledge base with tools like GWAS, it would seem appropriate to ask what next? Will a complete genome remove some of the guess work and mounting dependence on bioinformatics and biostatistics and come to rest decidedly alongside the surge of artificial intelligence and machine learning lurking in the background? Will convergences of this kind bring us even closer to nanomolecular genomic manipulation and editing by adding insights into chromatin structure?

Only time will tell and as Santiago finally realized, making the best use of what we have in the moment will dictate the course and consequences of the journey we are on.