Understanding the molecular basis of adaptation to the environment is a central question in evolutionary biology, yet linking detected signatures of positive selection to molecular mechanisms remains challenging. Here we demonstrate that combining sequence-based phylogenetic methods with structural information assists in making such mechanistic interpretations on a genomic scale. Our integrative analysis shows that positively selected sites tend to co-localise on protein structures and that

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... tively selected clusters are found in functionally important regions of proteins, indicating that positive selection can contravene the well-known principle of evolutionary conservation of functionally important regions. This unexpected finding, along with our discovery that positive selection acts on structural clusters, opens new strategies for the development of better models of protein evolution. Remarkably, proteins where we detect the strongest evidence of clustering belong to just two functional groups: components of immune response and metabolic enzymes. This gives a coherent picture of immune response and xenobiotic metabolism as the drivers of adaptive evolution of mammals.