Less than 2% of our genome is protein-coding DNA. The vast expanses of non-coding DNA make up the genome’s “dark matter”, where introns, repetitive and regulatory elements reside. Surprisingly, variation between individuals in non-coding regulatory DNA is emerging as a major factor in the genetics of numerous diseases and traits, yet very little is known about how such variations contribute to disease risk.

Studying the genetics of regulatory variation is technically challenging as regulatory elements can affect genes located tens of thousands of nucleotides away, and often, multiple distal regulatory variations, each with a very small effect, combine in an unknown way to significantly modulate the expression of genes.

The center for Synthetic Regulatory Genomics (SyRGe), a Center of Excellence in Genomic Science (CEGS), supported by the National Human Genome Research Institute (NHGRI), was established to directly tackle these problems and to systematically elucidate the mechanisms of regulatory variation in disease.

Genome wide association studies (GWAS) provide crude mileposts for the locations of human genome sequence variations that underlie disease susceptibility. However, they are like a dime-store compass – and we want Google maps style precision to find every variation that counts! With the technology we are developing, we should be able to pinpoint the exact variant or variants responsible for disease susceptibility. Armed with this knowledge, we can much more rapidly develop gene therapies and new drugs.

Even to biologists, gene regulation is so complex, it’s a bit like a computer to cavemen. Until recently, the only way to understand it was to remove or break its components, one at a time (which almost always just breaks the whole thing). Another way was to work with tiny bits and pieces divorced of their context. Not good. Our Big DNA technology changes all that. Now we can design and build that computer from the ground up with many subtle changes to any of its components, and as many as we like simultaneously. This revolutionary approach lets us tackle longstanding enigmas in the field of regulatory genomics.

Mice have been used to model human diseases for a long time, but mice, being mice, are not always suitable models. Their genes are similar, but not identical, to humans, and they are often regulated differently. With Big DNA we can replace whole mouse genes, including their regulatory regions, with their human counterparts. We can even replace whole pathways. Amazingly, the transcriptional factors that operate on these big DNAs in “trans” are so well conserved evolutionarily that this aspect of “mousiness” seems to work fine on the human genes – at least most of the time! These “humanized” mice are much better experimental models to understand diseases and to test new therapeutics. We call them GREAT-GEMMs (Genomically Rewritten and Tailored Genetically Engineered Mouse Models)!