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Koki, C.

Publications and source records attributed to Koki, C..

2 recordsLinked to original sources

Attenuation of mosaic aneuploidy and erroneous first mitotic division of human embryos

Human reproduction is inherently inefficient1 and 1 in 6 people worldwide suffer infertility. In vitro fertilisation (IVF) can help some couples conceive, but only ~30% of cycles are successful. One factor affecting IVF efficacy is mitotic-origin (mosaic) aneuploidy in which embryos contain a mixture of cells with different numbers of chromosomes2. We previously showed that chromosome segregation error phenotypes are frequent in the first mitotic division of the human embryo3. However, the cause of these errors and impact on daughter cell karyotype is unknown. Here, using live chromosome imaging and next generation sequencing we show that activation of the microtubule depolymerase KIF2C reduces chromosome segregation errors and mitotic-origin aneuploidy at the 2-cell stage. The number of first divisions that show alternative cleavage patterns (associated with failed embryo development in IVF clinics) are also reduced with KIF2C activation. Our findings demonstrate that modulation of microtubule dynamics is a potential therapeutic route to improving human embryo quality and IVF outcomes.

cell biology↗

Bayesian data driven modelling of kinetochore dynamics: space-time organisation of the human metaphase plate

Mitosis is a complex self-organising process that achieves high fidelity separation of duplicated chromosomes into two daughter cells through capture and alignment of chromosomes to the spindle mid-plane. Chromosome movements are driven by kinetochores, multi-protein machines that attach chromosomes to microtubules (MTs), both controlling and generating directional forces. Using lattice light sheet microscopy imaging and automated near-complete tracking of kinetochores at fine spatio-temporal resolution, we produce a detailed atlas of kinetochore metaphase-anaphase dynamics in untransformed human cells (RPE1). We determined the support from this dataset for 17 models of metaphase dynamics using Bayesian inference, demonstrating (1) substantial sister asymmetry that transversely organises the metaphase plate (MPP), (2) substantial spatial organisation of KT dynamic properties within the MPP, and (3) mechanical parameter time dependence, K-fiber forces tuning over the last 5 mins of metaphase towards a set point referred to as the anaphase ready state. These spatio-temporal trends are robust to spindle assembly pathways that are error-prone, suggesting the underpinning processes of kinetochore heterogeneity are intrinsic to mitosis and possibly by design.

systems biology↗