Despite many years of intensive research, we still know little about the genetics behind complex diseases like diabetes, obesity, and allergies. Three research groups from Uppsala and the US now describe a new genetic mechanism that sheds new light on the genetic background to complex disorders and other traits that are affected by both genes and environment.

The scientists have made use of a unique poultry population to provide a new answer to a question that has haunted researchers since the early 20th century: what are the genetic mechanisms that allow breeders to create new populations where every individual is more extreme than the most extreme individual in the population that they started breeding from?

Since 1957 Paul Siegel, at Virginia Tech in the US, has studied the biological effects of selection for extreme body weight in chickens. Starting from a homogeneous poultry population, he has bred two lines of chickens, one for high body weight and one for low body weight. In the high line, the heaviest animals were chosen to be the parents of the next generation, and in the low line the lightest individuals were chosen. Today the high line chickens weigh eight times as much as the low line chickens at eight weeks of age (see picture).

– This is one of the greatest responses to selection ever recorded in vertebrates and is considerably greater than disrupting the function of any of the individual genes that are known to have the largest impact on growth, says Leif Andersson, who initiated the genetic studies of poultry lines in collaboration with Paul Siegel.

The scientists have now managed to find a network of four coordinated genes that explains half of the difference between these two poultry lines.

– We have now analysed the data using a new method that takes into consideration how genes interact. Using this method we can explain considerably more of the differences between the lines than by using traditional methods. The major effects on growth are found only in those individuals who have certain specific combinations of gene variants for these four genes, says Örjan Carlborg, coordinator of the study.

This is the first time experimental data have successfully provided a mechanistic explanation for how interaction between genes can affect how populations are altered by natural or artificial selection.

– The results are not surprising, since it has long been suspected that interaction is important in the regulation of most biological traits, but this type of mechanism was not expected to play such a dominant role, says Örjan Carlborg.

The two poultry lines differ also in regard to other features than growth, such as appetite, obesity, and immune response. The high-line chickens are compulsive eaters, whereas the low-line chickens are anorectic; the high-line chickens are fat while the low-line chickens are slender; and the high line also has a weaker immune response than the low line.

– This is why we expect that this animal model will be extremely interesting for finding out whether the mechanism we have discovered might also underlie the regulation of the medically interesting metabolic and immmunological traits, including regulation of appetite, obesity, and immune response. This can provide new knowledge that may ultimately lead to improved drugs for many of our complex diseases, says Örjan Carlborg.

The findings are being published on the Nature Genetics home page on March 12. The authors are Örjan Carlborg, Lina Jacobsson, Per Åhgren, Paul Siegel, and Leif Andersson.

Örjan Carlborg, Center for Bioinformatics, phone: +46 18-471 66 91; cell phone: +46 704-25 03 87; e-mail: orjan.carlborg@lcb.uu.se