Detecting past positive selection through ongoing negative selection.

Detecting positive selection is a challenging task. We propose a method for detecting past positive selection through ongoing negative selection, based on comparison of the parameters of intraspecies polymorphism at functionally important and selectively neutral sites where a nucleotide substitution of the same kind occurred recently. Reduced occurrence of recently replaced ancestral alleles at functionally important sites indicates that negative selection currently acts against these alleles and, therefore, that their replacements were driven by positive selection. Application of this method to the Drosophila melanogaster lineage shows that the fraction of adaptive amino acid replacements remained approximately 0.5 for a long time. In the Homo sapiens lineage, however, this fraction drops from approximately 0.5 before the Ponginae-Homininae divergence to approximately 0 after it. The proposed method is based on essentially the same data as the McDonald-Kreitman test but is free from some of its limitations, which may open new opportunities, especially when many genotypes within a species are known.