The 23,000 protein-coding genes in the human genome can help determine whether a person will have blond hair or black, flat feet or arched. But that's hardly the whole story behind the millions of tiny differences among people. Most of the genome is so-called noncoding DNA, whose role in determining individual differences is only just starting to be understood.
Some of these sequences actually exert a big influence on how genes are expressed in different people, report the authors of a new study, published online March 18 in Science. Transcription factors, proteins that are cued by these noncoding DNA sequences, can bind to different areas that change gene expression, thereby altering how a single gene manifests in different people.
To detect some of these intricate variations, the researchers examined two transcription factors and how they adhered to numerous genes in 10 people. For the transcription factor NF-kB, which had some 15,000 binding sites, about 7.5 percent of them varied across people in the study. And for the other, RNA PolII, about a quarter of its 19,000 binding sites were altered across the sample. These levels of variability "greatly exceed estimates for sequence variation in coding sequences" of DNA, which varies by only 0.025 percent among all people, the researchers noted in their study. The small variations in transcription factor binding "have a profound impact on gene expression," Michael Snyder, of Stanford University and a co-author of the study, said in a prepared statement.
These findings open the door for a broader range of study of the human genome and related research, such as disease investigation. "As well as looking for disease genes, we could start looking at how genes are regulated, and how individual variations in gene regulation could affect patients' reactions," Jan Korbel, of the European Molecular Biology Laboratory and a co-author, said in a prepared statement.
The transcription factors appear to work not just on the genes, but also with each other. "These results suggest adjacent binding sites and [binding regions] may influence one another, perhaps through cooperative binding or interactions with other proteins," the researches wrote in their study.
"We are rapidly entering a time when nearly anyone can have his or her genome sequenced," Snyder said. "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."
Image of a binding protein courtesy of Wikimedia Commons/David Goddsell/Scripps Research Institute