Researchers worldwide are seeking to define ancient sections of our genetic code that may soon be as important to medical science as genes.
A new wave of research is concerned with, not how genes work, but how small regulatory DNA sequences tell genes where, when and to what degree to "turn on." As part of this effort, researchers at the University of Rochester Medical Center scanned through the vast human DNA code to reveal for the first time 60 genes influenced by one such sequence, according to an article published in the journal Genome Research.
Growing knowledge of how regulatory sequences control gene behavior has the potential to create new classes of treatment for nerve disorders and heart failure. Such sequences may also help to explain why humans are so complex, despite having one-fifth as much genetic material as wheat for instance. Medical center researchers are working on just one of more than 100 regulatory sequences identified so far, each the subject of intense study.
"Most people don't realize that genes make up a very small percentage of the human DNA code," said Joseph M. Miano, Ph.D., senior author of the journal paper and associate professor within the Cardiovascular Research Institute at the medical center. "Genes are relatively straightforward compared to what lies ahead. We believe that the real genetic gymnastics, the real intelligence of our system, is controlled by tiny bits of genetic material that tell genes what to do."
Genes are the chains of deoxyribonucleic acids (DNA) that encode instructions for the building of proteins, the workhorses that make up the body's organs and carry its signals. The Human Genome Project, which first reported results in 2001, produced a near complete listing of the DNA sequences that make up all human genes (the genome). Key project findings included that human genetic material consists of about 3 billion base pairs, the "letters" that make up the genetic code. Researchers also concluded that genes, specific batches of code that direct protein construction, comprise just about 2 percent of all human DNA. A central question in genetics has become: what does the remaining 98 percent of human genetic material do?
Regulatory sequences are emerging as an important part of the non-gene majority of human genetic material, once thought of as "junk DNA." A new frontier in genetic research is the defining of the regulome, the complete set of DNA sequences that regulate the behavior of genes. DNA segments that code for proteins average 200 base pairs in length, whereas regulatory sequences typically include just six to 10 base pairs, making them hard to find.
As a human embryo develops from a single cell into tens of billions of cells, DNA must be read and copied again and again to supply each cell with its needed copy. Over time, random changes, or mutations, are inserted into the code during the copying process. Some mutations bring survival advantages and others cause disease. Most known genetic diseases identified to date result from a mutation within a gene that directs protein construction, but that may soon change.
"We believe more and more disease-causing mutations will be found within regulatory sequences that control genes turning on or off," Miano said. "We therefore are very interested in defining as many functional regulatory elements as we can to help geneticists pinpoint a growing number of disease-causing mutations."
In Miano's study, the regulatory sequence under examination was the CArG box. The nucleotide building blocks of DNA chains may contain any one of four nucleobases: adenine (A), thymine (T), guanine (G) and cytosine (C). Any sequence of code starting with 2 Cs, followed by any combination of 6 As or Ts, and ending in 2 Gs is a CArG box.
According to Miano, there are 1,216 variations of CArG box that together occur approximately three million times throughout the human DNA blueprint.
CArG boxes exert their influence over genes because they are "shaped" to partner with a nuclear factor called serum response factor (SRF) and several other proteins within a genetic regulatory network. Throughout a human life, such networks are believed to "decide" the timing and location of all gene expression, the process through which genetic information is converted into templates for protein construction.
The current study, funded through a grant from the National Heart, Lung and Blood Institute, sought to survey the human and mouse genome databases created by the Human Genome Project to find all CArG boxes that regulate genes. The sheer amount of information involved requires that such studies use high-powered computer programs to screen data. In this case, researchers used a high-speed screening to expand the definition of the functional mammalian CarGome, the complete set of CArG boxes that regulate genes.