Positive selection on the insulin signal transduction pathway across human populations

The insulin/TOR signal transduction pathway is involved in metabolic disorders such as obesity, insulin resistance and diabetes. The prevalence of such disorders is dramatically different among human populations. Therefore, applying population genetics analysis to describe how natural selection acted in different populations on the genes involved in this pathway may provide key insight into the etiology of these diseases.

A recent paper published in Molecular Biology and Evolution does just that. The authors, from Jaume Bertranpetit’s lab at the Institute of Evolutionary Biology (IBE: CSIC-UPF), have combined genotype data from nearly 1,000 individuals from 39 human populations from around the world with current knowledge of the structure and function of the insulin/TOR pathway. Their aim was to analyse the patterns of molecular evolution of 67 genes involved in that pathway.

They identified the footprint of recent positive selection in nine of the studied genes. Looking at the network position of the proteins coded by those genes, they found that positive selection (that is, a favourable selection which ensures that the affected genes/alleles will increase) preferentially targets the most central elements in the pathway. This result is in contrast to previous observations using the whole human interactome, which had found that peripheral elements of the network were more targeted by positive selection.  Therefore, the authors conclude, “the structure of the pathway influences the patterns of molecular evolution of its components”.

“We worked with a hand-curated data set, minimizing the possibility of mis-annotation interactions among proteins. We looked at polymorphisms within different populations worldwide for genes encoding proteins involved in the insulin/TOR pathway. The fact that we focussed our work at intra-specific level makes it fairly unique in the field of network evolution. This systems biology approach is a nice and robust way of understanding human diseases through the study of human evolution”, says first author Pierre Luisi.

Luisi P, Alvarez-Ponce D, Dall’olio GM, Sikora M, Bertranpetit J, & Laayouni H (2011). Network-level and population genetics analysis of the insulin/TOR signal transduction pathway across human populations. Molecular Biology and Evolution PMID: 22135191


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