Lineage tracing of the human brain

ongoing

Organisms develop through cell divisions generating clones that progressively organize to form different tissues. This process can be visualized as a cell phylogeny by lineage tracing. In order to track cell lineages, each cell division has to be permanently and uniquely marked. In model systems, this is done by genome editing. In humans this is not applicable, which has historically made impossible to accurately study cell phylogenies. Very recently, however, studies showed that human tissues contain a set of natural markers in the form of somatic DNA variants that permanently and cumulatively label every cell division during development. My work showed that somatic variants are reliable at tracking cell lineages directly in human tissues. Human brain development has historically been difficult to address since human-brain-specific features are hardly recapitulated in any existing model. My project now builds on the use of somatic variants to reveal the cellular processes that form the brain starting from available human material. Somatic variants will be identified at unprecedent sensitivity in a large set of human foetal tissues, including multiple different brain regions. In work package (WP)1, I will identify and study the lineage segregation steps defining the brain phylogeny starting from the zygote. Mathematical modelling will elucidate mechanisms of clone dynamics. In WP2, I will focus on the cerebral cortex and reconstruct cell phylogenies of neural progenitors and the distribution of cortical clones. Furthermore, I will compare normal versus overgrowth cortical malformation brains, where cell proliferation and migration are altered. In WP3, I will develop new strategies to simultaneously assess cell phylogenies and cell-type specification by identifying somatic variants in multi-omics data. This project will reveal the unfolding of the cellular lineages building the human brain, while providing a methodology that is applicable to any tissue and pathology.