GenRevo · Genetic Engineering of Regulatory Evolution

The regulation of genes is generally accepted to play a key role in shaping phenotypes. However, how regulatory sequence encodes complex morphological structures remains unsolved. This is due to our lack of understanding of how enhancers, promoters, and other regulatory components work together to control and fine-tune gene expression. As such, one of the major challenges of the post-genomic era is to uncover the sequence code that controls gene expression and, ultimately, the phenotype. In GenRevo, I propose to study the genomics of an extreme example of evolutionary adaption, the wings of bats, as a model system to identify and functionally dissect how sequence determines phenotype. Our approach involves the genetic re-engineering of bat regulatory sequence in mice and their functional dissection to identify the essential components that govern gene expression and phenotype.Based on an already generated comprehensive data set from mouse and bat limb buds, we will detect, re-engineer and dissect intra- and interspecies differences in regulatory landscapes linked to batwing development. In particular, we will 1) determine what non-coding features are essential for maintenance and/or change in gene expression, 2) reconstitute bat-specific regulatory landscapes in mice by genome engineering synthetically produced large DNA sequences, 3) dissect how genomic changes translate into altered gene expression and phenotypes on cellular and regulatory level, and 4) create de novo designer regulatory landscapes that can be used as a testbed for experimental perturbations. Collectively, GenRevo will produce ground-breaking knowledge in our understanding of how gene regulatory units work in vivo and how variants influence phenotypes. The possibility to re-engineer sequences in another species will spark a technological revolution in the functional analysis of mammalian genomes, particularly regarding the function of non-coding DNA in human diseases, traits, and evolution.