A research at the Wellcome Trust Sanger Institute suggests that common, complex human diseases are more likely to occur due to genetic variation in regions that control activity of genes, rather than in the regions that specify the protein code.
The surprising findings are based on a study of almost 14,000 genes in 270 DNA samples collected for the HapMap Project, an international organisation whose goal is to develop a haplotype map of the human genome, which will describe the common patterns of human genetic variation.
The study's authors looked at 2.2 million DNA sequence variants (SNPs) to determine which affected gene activity. They found that over 1300 genes had had their activity affected due to DNA sequence changes in regions predicted to be involved in regulating gene activity.
"We predict that variants in regulatory regions make a greater contribution to complex disease than do variants that affect protein sequence. This is the first study on this scale and these results are confirming our intuition about the nature of natural variation in complex traits," Nature magazine quoted Dr Manolis Dermitzakis, senior author from the Wellcome Trust Sanger Institute, as saying.
"One of the challenges of large-scale studies that link a DNA variant to a disease is to determine how the variant causes the disease: our analysis will help to develop that understanding, a vital step on the path from genetics to improvements in healthcare," he added.
According to the authors, the regions where they noticed DNA sequence changes often lie close to, but outside, the protein-coding regions. "We found strong evidence that SNP variation close to genes - where most regulatory regions lie - could have a dramatic effect on gene activity. Although many effects were shared among all four HapMap populations, we have also shown that a significant number were restricted to one population," said Dr Barbara Stranger, post-doctoral fellow at WT Sanger Institute.
The study has also shown that gene that are required for the basic functions of the cell, known as housekeeping genes, are less likely to be subject to genetic variation.
"This was exactly as we would expect: you can't mess too much with the fundamental life processes and we predicted we would find reduced effects on these genes," said Dr Dermitzakis.
The researchers also observed that SNP variants that affect the activity of genes located a great distance away. They believe that a tool to detect such distant effects may expand the search for causative variants.
However, the study's authors say that the small sample size of 270 HapMap individuals is sensitive enough to detect only the strongest effects.
The study's findings are available in public databases such as Ensembl, so that researchers may use them.