impMKT: the imputed McDonald and Kreitman test, a straightforward correction that significantly increases the evidence of positive selection of the McDonald and Kreitman test at the gene level

The McDonald and Kreitman test is one of the most powerful and widely used methods to detect and quantify recurrent natural selection in DNA sequence data. One of its main limitations is the underestimation of positive selection due to the presence of slightly deleterious variants segregating at low frequencies. Although several approaches have been developed to overcome this limitation, most of them work on gene pooled analyses. Here, we present the imputed McDonald and Kreitman test (impMKT), a new straightforward approach for the detection of positive selection and other selection components of the distribution of fitness effects at the gene level. We compare imputed McDonald and Kreitman test with other widely used McDonald and Kreitman test approaches considering both simulated and empirical data. By applying imputed McDonald and Kreitman test to humans and Drosophila data at the gene level, we substantially increase the statistical evidence of positive selection with respect to previous approaches (e.g. by 50% and 157% compared with the McDonald and Kreitman test in Drosophila and humans, respectively). Finally, we review the minimum number of genes required to obtain a reliable estimation of the proportion of adaptive substitution (a) in gene pooled analyses by using the imputed McDonald and Kreitman test compared with other McDonald and Kreitman test implementations. Because of its simplicity and increased power to detect recurrent positive selection on genes, we propose the imputed McDonald and Kreitman test as the first straightforward approach for testing specific evolutionary hypotheses at the gene level. The software implementation and population genomics data are available at the web-server imkt.uab.cat.