Genomic variation does not only include nucleotide changes, it also comprises changes in DNA shape, structure, epigenetic marks, and expression, all of which can occur over generations, cellular differentiation, the span of a few hours or a few millennia. This doctoral thesis explores the implications and opportunities presented by these multiple forms of genomic variation for genome editing, cellular differentiation, genome regulation and comparative genomics, all towards improving our understanding of genome evolution and development and benefiting human health.