Study maps disease-linked gene variants

Single-letter changes in DNA found in regulatory regions of genes

MONTREAL — Many genetic variants linked to disease may play a role in regulating gene activity rather than altering the gene itself, new evidence suggests.

In recent years, scientists have discovered genetic variants associated with a wide variety of diseases, but in most cases it has not been clear exactly how the variant leads to disease.

“One of the problems with [these] studies is that we’re getting all of these statistical signals, but we don’t know the underlying biology,” said Emmanouil Dermitzakis of the University of Geneva in Switzerland.

Single-letter changes in a gene’s DNA, known as SNPs for single nucleotide polymorphisms, can sometimes change the composition and function of proteins built from the gene’s instructions. But often these variations don’t fall within the protein-producing parts of genes, or they don’t alter the protein.

Some researchers have proposed that many of these SNPs may change the way genes are regulated. Now, John Stamatoyannopoulos of the University of Washington in Seattle and colleagues have found evidence that more than half of disease-associated SNPs map to parts of the genome that govern gene activity.

Stamatoyannopoulos’ group first mapped out parts of the genome where regulatory proteins tasked with turning genes on and off latch onto DNA. At those spots, DNA is relatively naked and open to a DNA-cutting enzyme known as DNAse I. It turns out that spots in the genome where the enzyme cuts easily are the same places where known gene-regulating proteins grab DNA, Stamatoyannopoulos said October 13 at the International Congress of Human Genetics.

The researchers then compared the regulatory sites with the locations of disease-associated SNPs and found that 53 percent of disease-linked variants map to the regulatory sites. Another 22 percent of disease-associated SNPs are located near such regulatory sites. Many of these SNPs are associated with pieces of DNA that are important for regulating genes during development, suggesting that early differences in gene activity may influence health later in life, Stamatoyannopoulos said.

The researchers still need to confirm whether these genetic spelling differences alter gene activity and if changes in gene activity are responsible for the development of disease.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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