Finding: A new study shows that common, complex diseases are more likely to be due to genetic variation in regions that control activity of genes, rather than in the regions that specify the protein code.
Where are the regions?
This result comes from a study of the activity of almost 14,000 genes in 270 DNA samples collected for the HapMap Project. The authors looked at 2.2 million DNA sequence variants (SNPs) to determine which affected gene activity. They found that activity of more than 1300 genes was affected by DNA sequence changes in regions predicted to be involved in regulating gene activity, which often lie close to, but outside, the protein-coding regions.
The challenge of large-scale studies that link a DNA variant to a disease
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.
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.
What the HapMap does
Past studies of rare, monogenic disease, such as cystic fibrosis and sickle-cell anaemia, have focused on changes to the protein-coding regions of genes because they have been visible to the tools of human genetics. With the HapMap and large-scale research methods, researchers can inspect the role of regions that regulate activity of many thousands of genes.
The HapMap Project established cell cultures from participants from four populations as well as, for some samples, information from families, which can help to understand inheritance of genetic variation. The team used these resources to study gene activity in the cell cultures and tie that to DNA sequence variation
Scientists 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, they also shown that a significant number were restricted to one population.
What about the house keeping genes?
They also showed that genes required for the basic functions of the cell - so-called housekeeping genes - were less likely to be subject to genetic variation. This was exactly as one would expect: you can't mess too much with the fundamental life processes and we predicted we would find reduced effects on these genes.
The study also detected SNP variants that affect the activity of genes located a great distance away. Genetic regulation in the human genome is complex and highly variable: a tool to detect such distant effects will expand the search for causative variants. The authors note, however, that the small sample size of 270 HapMap individuals is sensitive enough to detect only the strongest effects.