Variability in Transcription Factor Binding Can Make You Look Like a Monkey if You Pay for Expensive Gene Sequencing

The ready availability of gene sequencing promises to bring in a new era in medicine.  But expensive gene sequences may not tell you what you really want to know.  Underlying phenomena such as transcription factor binding, non-coding RNAs, copy number variant, and other more shadowy aspects of gene expression may hold the secret keys to more subtle aspects of why you are the way you are.

"We are rapidly entering a time when nearly anyone can have his or her genome sequenced," said Michael Snyder, PhD, professor and chair of genetics at Stanford. "However, the bulk of the differences among individuals are not found in the genes themselves, but in regions we know relatively little about. Now we see that these differences profoundly impact protein binding and gene expression."

Snyder is the senior author of two papers -- one in Science Express and one in Nature -- exploring these protein-binding differences in humans, chimpanzees and yeast. Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, came to Stanford in July 2009 from Yale, where much of the work was conducted.

Genes, which carry the specific instructions necessary to make proteins do the work of the cell, vary by only about 0.025 percent across all humans. Scientists have spent decades trying to understand how these tiny differences affect who we are and what we become. In contrast, non-coding regions of the genome, which account for approximately 98 percent of our DNA, vary in their sequence by about 1 to 4 percent. But until recently, scientists had little, if any, idea what these regions do and how they contribute to the "special sauce" that makes me, me, and you, you.

Now Snyder and his colleagues have found that the unique, specific changes among individuals in the sequence of DNA affect the ability of "control proteins" called transcription factors to bind to the regions that control gene expression. As a result, the subsequent expression of nearby genes can vary significantly. _SD

The Stanford team is only scraping the surface of the complexity of gene expression, but they are making progress. For members of the public it would be easy to become obsessed with the marvels of gene sequencing, and to overlook the fact that the gene sequence is just the bare beginning of understanding gene expression. A crucially important beginning, yes, but still a small one.