Junk DNA and genomic stability

Duke researchers discover connection between junk DNA variations and increased risk of cancer or other diseases

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DURHAM, N.C.—Researchers at the Duke University School of Medicine have discovered that variations in the chromosome’s “junk DNA” affect the stability of the genome, leading to an increased risk of cancer or other diseases.
Among the many pieces of so-called junk DNA—the long stretches of repetitive genetic code not yet included in the mapping of the genome—is the centromere, the tie that holds a pair of chromosomes together in a floppy X shape and coordinates their movement during cell division. Researchers once believed that each chromosome contained a single stretch of the repeated 171-base pair units, or satellite DNA, which determined where its centromere would reside. But in 2012, a research team led by Dr. Beth A. Sullivan, an associate professor of molecular biology and microbiology at Duke University School of Medicine, discovered that many human chromosomes possessed more than one of these regions, and depending on the individual, the centromere could form at either site.
Now, in a study published online in August in Genome, Sullivan’s team has shown that variations in the size or sequence of either of the satellite DNA determine the placement of the centromere at a primary position or a less stable “backup” site nearby.
Sullivan’s team focused its efforts on chromosome 17, mutations in which are often implicated in birth defects and cancers. Using samples they tested from a human DNA bank, the researchers determined that about 70 percent of humans had no variation at the primary site, and 30 percent had some degree of variation. Most of the time, they found, the centromere is not built at the primary site if variation is present, but at the backup site. That can result in architecturally unsound centromere, which in turn can affect the soundness of the chromosome.
“It is immensely fascinating to think that there are so many people walking around who are essentially centromere mosaics,” said Sullivan. “One of their centromeres, on one of their chromosomes, has the potential to be dangerously unstable, and it could affect their ability to reproduce, or predispose them to cancer.”
Sullivan also suggests that this study may change the direction of research on the centromere, which had to this point discounted the effect of DNA in favor of that of proteins on their development and function. That model, she says, “posits that as long as the correct collection of proteins assemble together, they can do so on any DNA sequence. However, studies from my lab and others showed that making new centromeres from scratch (i.e. human artificial chromosomes) only works on repetitive alpha satellite DNA, suggesting that DNA sequence is important to some extent in centromere function.”
The team plans in the future to study the size of the risk posed by the variations in this satellite DNA and to possibly develop a way to use these sequences as biomarkers for the chromosomal defects that can lead to disease. And, as this research has only been applied to one of the 23 pairs of human chromosomes, the future is wide open.
“What we found in this study is probably the tip of the iceberg,” Sullivan said. “There could be all sorts of functional consequences to having variation within the complex, repetitive portion of the genome that we don’t know about yet.”
In other Duke news, the Duke Clinical Research Institute (DCRI) and Boehringer Ingelheim have recently announced the expansion of the Idiopathic Pulmonary Fibrosis—PROspective Outcomes (IPF-PRO) Registry, a patient registry developed to uncover insights into IPF, a rare and serious lung disease that causes permanent scarring of the lungs and affects as many as 132,000 Americans, typically men over the age of 65.
The IPF-PRO Registry was launched in June 2014 as the first multicenter longitudinal disease state registry in the United States focused specifically on IPF. According to press materials, Boehringer Ingelheim and the DCRI have agreed to expand the IPF-PRO Registry based on the success of the registry in providing data and insights from its first 300 patients, as well as the growing need for data from a larger and more geographically diverse IPF patient group, to better understand IPF disease progression, disease history, patient-reported outcomes and disease biomarkers.
The expansion will take the study enrollment from the current 300 patients at 18 study sites to 1,500 patients at approximately 45 sites, which will create the largest registry of newly diagnosed IPF patients. Part of the purpose of the expansion is to increase the size of the bio-repository of blood samples that provide patient genetic material that may help researchers better understand the relationship of various biomarkers to patient outcomes.

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