Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy

Biswas, Leelabati; Tyc, Katarzyna M.; Aboelenain, Mansour; Sun, Siqi; Dundović, Iva; Vukušić, Kruno; Liu, Jason; Guo, Vanessa; Xu, Min; Scott, Richard T.; Tao, Xin; Tolić, Iva M.; Xing, Jinchuan; Schindler, Karen (2024) Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy. Proceedings of the National Academy of Sciences, 121 (45). ISSN 0027-8424

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	aneuploidy; KIF18A; meiosis
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Molecular Biology
Projects:	Project title Project leader Project code Project type Molecular origins of aneuploidies in healthy and diseased human tissues-ANEUPLOIDY Iva Tolić; Nenad Pavin 855158 EK Kako starost centrosoma utječe na stvaranje, popravak i segregaciju polarnih kromosoma Iva Marija Tolić IPCH-2022-10-9344 HrZZ Inovativni protokoli mikroskopije za interdisciplinarna istraživanja u biomedicini-IPSted Iva Tolić KK.01.1.1.04.0057 EK Provedba vrhunskih istraživanja u sklopu Znanstvenog centra izvrsnosti za kvantne i kompleksne sustave te reprezentacije Liejevih algebri-QuantiXLie Hrvoje Buljan; Pavle Pandžić; Vit Tuček; Tomislav Marketin KK.01.1.1.01.0004 EK
Depositing User:	Lorena Palameta
Date Deposited:	30 Jul 2025 10:29
URI:	http://fulir.irb.hr/id/eprint/9936
DOI:	10.1073/pnas.2414963121

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