TempShift Reveals the Sequential Development of Human Neocortex and Skewed Developmental Timing of Down Syndrome Brains

Abstract

Development is a complex process involving precise regulation. Developmental regulation may vary in tissues and individuals, and is often altered in disorders. Currently, the regulation of developmental timing across neocortical areas and developmental changes in Down syndrome (DS) brains remain unclear. The changes in regulation are often accompanied by changes in the gene expression trajectories, which can be divided into two scenarios: (1) changes of gene expression trajectory shape that reflect changes in cell type composition or altered molecular machinery; (2) temporal shift of gene expression trajectories that indicate different regulation of developmental timing. Therefore, we developed an R package TempShift to separates these two scenarios and demonstrated that TempShift can distinguish temporal shift from different shape (DiffShape) of expression trajectories, and can accurately estimate the time difference between multiple trajectories. We applied TempShift to identify sequential gene expression across 11 neocortical areas, which suggested sequential occurrence of synapse formation and axon guidance, as well as reconstructed interneuron migration pathways within neocortex. Comparison between healthy and DS brains revealed increased microglia, shortened neuronal migration process, and delayed synaptogenesis and myelination in DS. These applications also demonstrate the potential of TempShift in understanding gene expression temporal dynamics during different biological processes.