PAX6 as a model for synthetic hypervariation studies

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The regulation of human gene expression during development is controlled by genetic switch elements called enhancers. Enhancers are often located at huge (100 to 1000kb) genomic distance from their target genes and genes important in development have many tens of such elements controlling gene expression in different cell types, different tissues and at different times. This represents a fundamental "Rule of Life" that we do not understand well at all. To help establish a platform to systematically address such a profound basic question about how our genome controls development, we will use a systematic synthetic genomic approach. This allows multiple variations of a large portion of the human genome (five hundred thousand base pairs) to be constructed with great precision in yeast cells. Then the variants will be precisely delivered to the vertebrate genome to test whether and how the engineered synthetic variants work during development. For our study, we have chosen the key gene required for eye development - PAX6.