The growing understanding of the human genome has fostered a notion that genetic inheritance predicts an inevitable fate: yet it is widely known that identical twins, thought to be genetically identical, are as notable for their uniqueness from each other as for their similarities. This presents the question: how are humans constituted so that genetic endowment is not simply deterministic?
Our work shows that during normal human development, each dividing cell propagates mutations to its daughter cells until a mosaic human of ten trillion imperfect cells, each with its own unique genome, is produced. Thus, every human contains a permanent map, encoded by mutations during cell division, of the lineage that generates every cell in the body. However, reading out that map requires new technology that allows simultaneous analysis of DNA mutations (which encode the lineage map) and analysis of RNA (which identifies the cell). We are developing methods to capture RNA and DNA data from single cells of postmortem human brains at high throughput that will allow us to read the map of human brain development, understand how genomic diversity influences the function of the genome, and provide new tools that enable an understanding of the unique patterns of development of each individual.
The unexplored Big Questions are: to what extent is brain mosaicism always bad? In other words, does the diversity created by mutations that lead to brain mosaicism have positive aspects, too? Are somatic mutations also a source of individual uniqueness? Does this diversity relate to unique differences between identical twins who are conceived with an identical genetic blueprint? Since the rates and types of mutation are clearly under evolutionary selection, are the mosaic mutations in the brain a tolerated byproduct of some other purpose, or is the behavioral and cognitive diversity created by these mutations advantageous?
