Capalbo, A. | Search bioRxiv

bioRxiv2025

Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans

Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent-of-origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocysts embryos generated by intra-cytoplasmic sperm injection (ICSI), we estimate that 1.1% of human conceptions (n=1,063) contain extra or missing chromosome sets in zygotes. We identify a maternal age effect, with a 1.059 per year increased risk in triploidy/haploidy (p=0.0008). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p=0.03). Genotype analysis of 55 triploid embryo biopsies and their parents show that one third of maternal triploid conceptions originate in meiosis I and two thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome-wide, suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a new type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41 of 74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.

genetics↗

bioRxiv2020

Autoregulatory circuit regulating basolateral cargo export from the TGN: role of the orphan receptor GPRC5A in PKD signaling and cell polarity.

The membrane transport apparatus comprises a series of separate membrane bound compartments, or transport stations, that are responsible for the synthesis, processing, transport, sorting and delivery to their final cellular destinations of most transmembrane and soluble lumenal proteins. Over the last decades the membrane transport system has been shown to be extensively regulated both by environmental inputs and by internal homeostatic signalling systems, or control systems, that operate to maintain the homeostasis and optimal functionality of the main transport stations, such as the endoplasmic reticulum and the Golgi, in the face of internal and external perturbations. The trans-Golgi network (TGN) is a major transport and processing station and the main sorting compartment of the transport apparatus. However, the mechanisms that control cargo export and sorting at the TGN have so far remained elusive. Here we focus on the sorting of basolateral cargo proteins and show that these proteins bind to the TGN localized orphan receptor GPRC5A. The cargo-GPRC5A complex triggers the activation of a signaling pathway that involves the G{beta}{gamma} subunits dependent activation of the phospholipase C beta 3 (PLC{beta}3), which inturn induces diacyl glycerol (DAG) production. DAG recruits and activates protein kinase D (PKD) and the phosphorylation of its substrates. This step results in the formation of basolateral carriers for delivery of these cargoes to the basolateral plasma membrane domain. We term this mechanism "ARTG" (AutoRegulation of TGN export). Remarkably, the impairment of ARTG pathway components, and in particular of GPRC5A, causes defects in the polarized organization of epithelial cells.

cell biology↗