An official website of the United States government
The female reproductive lifespan is highly dependent on egg quality, especially the presence of a normal number of chromosomes in an egg, known as euploidy. Mistakes in meiosis leading to egg aneuploidy are frequent in humans. Yet, knowledge of the precise genetic landscape that causes egg aneuploidy in women is limited, as phenotypic data on the frequency of human egg aneuploidy are difficult to obtain and therefore absent in public genetic datasets. Here, we identify genetic determinants of reproductive aging via egg aneuploidy in women using a biobank of individual maternal exomes linked with maternal age and embryonic aneuploidy data. Using the exome data, we identified 404 genes bearing variants enriched in individuals with pathologically elevated egg aneuploidy rates. Analysis of the gene ontology and protein–protein interaction network implicated genes encoding the kinesin protein family in egg aneuploidy. We interrogate the causal relationship of the human variants within candidate kinesin genes via experimental perturbations and demonstrate that motor domain variants increase aneuploidy in mouse oocytes. Finally, using a knock-in mouse model, we validate that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings reveal additional functional mechanisms of reproductive aging and shed light on how genetic variation underlies individual heterogeneity in the female reproductive lifespan, which might be leveraged to predict reproductive longevity. Together, these results lay the groundwork for the noninvasive biomarkers for egg quality, a first step toward personalized fertility medicine.
more »
« less
Reproductive genomics of the mouse: implications for human fertility and infertility
Genetic analyses of mammalian gametogenesis and fertility have the potential to inform about two important and interrelated clinical areas: infertility and contraception. Here, we address the genetics and genomics underlying gamete formation, productivity and function in the context of reproductive success in mammalian systems, primarily mouse and human. Although much is known about the specific genes and proteins required for meiotic processes and sperm function, we know relatively little about other gametic determinants of overall fertility, such as regulation of gamete numbers, duration of gamete production, and gamete selection and function in fertilization. As fertility is not a binary trait, attention is now appropriately focused on the oligogenic, quantitative aspects of reproduction. Multiparent mouse populations, created by complex crossing strategies, exhibit genetic diversity similar to human populations and will be valuable resources for genetic discovery, helping to overcome current limitations to our knowledge of mammalian reproductive genetics. Finally, we discuss how what we know about the genomics of reproduction can ultimately be brought to the clinic, informing our concepts of human fertility and infertility, and improving assisted reproductive technologies.
more »
« less
- Award ID(s):
- 1942620
- PAR ID:
- 10394603
- Editor(s):
- Eve, Alex
- Date Published:
- Journal Name:
- Development
- ISSN:
- 1477-9129
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Advances in genetics and genomics have raised new questions in trout restoration and management, specifically about species identity and purity, which fish to value, and where these fish belong. This paper examines how this molecular turn in fisheries management is influencing wild and native trout policy in Colorado. Examples from two small Colorado watersheds, Bear Creek and Sand Creek, illustrate how framing trout as genetic bodies can guide managers to care for or kill trout populations in the interest of rectifying decades of genetic disruption caused by human activity. While trout management has typically relied on human intervention, the turn to genetic science is prompting new classifications of lineage and taxa, altering long-standing conservation priorities, and reorienting the manipulation of biological processes such as reproduction and dispersal. As a result, other social and ecological factors may be pushed to the margins of management decisions. These changes warrant greater conversation about the consequences of molecular analyses and the values embedded in trout science and conservation more broadly.more » « less
-
Abstract Regulations governing assisted reproduction control the degree to which gamete donation is legal and how people providing genetic material are selected and compensated. The United States and Spain are both global leaders in fertility treatment with donor oocytes. Yet both countries take different approaches to how egg donation is regulated. The US model reveals a hierarchically organized form of gendered eugenics. In Spain, the eugenic aspects of donor selection are more subtle. Drawing upon fieldwork in the United States and Spain, this article examines (1) how compensated egg donation operates under two regulatory settings, (2) the implications for egg donors as providers of bioproducts, and (3) how advances in oocyte vitrification enhances the commodity quality of human eggs. By comparing these two reproductive bioeconomies we gain insight into how different cultural, medical, and ethical frameworks intersect with egg donor embodied experiences.more » « less
-
Abstract Interactions between spermatozoa and the female reproductive tract (FRT) are complex, in many cases poorly understood, and likely to contribute to the mechanistic basis of idiopathic infertility. As such, it is not surprising that the FRT was often viewed historically as a “hostile” environment for spermatozoa. The FRT has also been touted as a selective environment to ensure that only the highest quality spermatozoa progress to the oocyte for the opportunity to participate in fertilization. Recent advances, however, are giving rise to a far more nuanced view in which supportive spermatozoa × FRT interactions—in both directions—contribute to beneficial, even essential, effects on fertility. In this perspective article, we discuss several examples of positive spermatozoa × FRT interactions. We believe that these examples, arising in part from studies of taxonomically diverse nonmammalian systems, are useful to efforts to study mammalian spermatozoa × FRT interactions and their relevance to fertility and the advancement of assisted reproductive technologies.more » « less
-
Abstract Sex is a crucial process that has molecular, genetic, cellular, organismal, and population‐level consequences for eukaryotic evolution. Eukaryotic life cycles are composed of alternating haploid and diploid phases but are constrained by the need to accommodate the phenotypes of these different phases. Critical gaps in our understanding of evolutionary drivers of the diversity in algae life cycles include how selection acts to stabilize and change features of the life cycle. Moreover, most eukaryotes are partially clonal, engaging in both sexual and asexual reproduction. Yet, our understanding of the variation in their reproductive systems is largely based on sexual reproduction in animals or angiosperms. The relative balance of sexual versus asexual reproduction not only controls but also is in turn controlled by standing genetic variability, thereby shaping evolutionary trajectories. Thus, we must quantitatively assess the consequences of the variation in life cycles on reproductive systems. Algae are a polyphyletic group spread across many of the major eukaryotic lineages, providing powerful models by which to resolve this knowledge gap. There is, however, an alarming lack of data about the population genetics of most algae and, therefore, the relative frequency of sexual versus asexual processes. For many algae, the occurrence of sexual reproduction is unknown, observations have been lost in overlooked papers, or data on population genetics do not yet exist. This greatly restricts our ability to forecast the consequences of climate change on algal populations inhabiting terrestrial, aquatic, and marine ecosystems. This perspective summarizes our extant knowledge and provides some future directions to pursue broadly across micro‐ and macroalgal species.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1242/dev.201313
