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Cellular pathways determining growth and human brain size

Final Report Summary - HUMGENSIZE (Cellular pathways determining growth and human brain size)

Organism size is a key outstanding developmental question. It is the biggest difference between mammals, with a 75 million fold difference between the smallest (bumble-bee bat) and largest (blue whale). Using a ‘human as a model organism’ approach, we have been studying a group of disorders of extreme growth failure (microcephalic dwarfism). The work funded by the ERC grant has led to the identification of 10 new disease genes for this group of conditions. This has enabled better diagnosis for European patients and assisted management by their local clinicians. Furthermore, this has provided insights into the underlying cell biology, establishing that genes involved in cell-cycle progression and genome stability are critical for ensuring organism growth in humans. This work has also contributed to establishing cerebral organoids (mini-brain) technology, allowing the study of developmental processes within a culture dish, to provide scientific insights that are not possible by other technologies. Finally, two of the genes identified in this work encode novel genome stability genes. Such genes are important in protecting DNA from damage during replication, and therefore may have wider biomedical interest given the importance of genome stability mechanisms in preventing cancer.