Other, larger differences in the genome, called structural variation, also accounted for a number of the differences in transcription factor binding. Structural variation happens when large segments of the genome are deleted, duplicated, or inverted. It varies widely among humans, and the role of such variability in human biology is not well understood.

But the new study shows that SNPs and structural variation can either increase or decrease transcription factor binding, and, hence, the amount of a protein that gets made from a particular gene. "We found that about one third of the differences in binding was caused by SNPs and structural variation," Snyder says. "This is the first time anyone has shown that SNPs and structural variation affect large number of regulatory elements that control gene expression. Normally, people look at differences in the gene themselves rather than in the regulatory regions, because they are difficult to identify."

The study also reports differences in binding of RNA polymerase II and NFkappaB near genes implicated in many major diseases, including type 1 diabetes, lupus, chronic lymphatic leukemia, schizophrenia, asthma, Crohn's disease, and rheumatoid arthritis. "Variation in the regulation of genes might eventually help account for some of the varying susceptibility to diseases we see in the population," Kasowski says.

In addition to looking at humans, Kasowski, Snyder and their colleagues looked at transcription factor binding for a single chimpanzee. The study shows that 32 percent of RNA polymerase II binding regions differed between the humans in the study and the chimp. Snyder says that he included the chimp out of curiosity to see how transcription factor binding might account for differences between ourselves and our closest genetic cousin. But the 32 percent difference between chimps and humans was not that much larger than the 25 percent difference in RNA polymerase II binding found among two individuals.

Still, Snyder says that the study opens a new genomic frontier for biologists. "Only about two percent of our DNA codes for genes," he says. "Studying the rest of the genome, including gene regulation and transcription factors, is the next wave in understanding human variation."

Source: Howard Hughes Medical Institute