Large-Scale Comparative Analysis of Codon Models Accounting for Protein and Nucleotide Selection

Abstract

There are numerous sources of variation in the rate of synonymous substitutions inside genes, such as direct selection on the nucleotide sequence, or mutation rate variation. However the majority of the codon models which are developed and widely used today still incorporate an assumption of effectively neutral synonymous substitution rate, constant between sites of each gene. Here we propose a simple yet effective extension to codon models, which incorporates codon substitution rate variation along the gene sequence. We find strong effects of substitution rate variation on positive selection inference. We also demonstrate that the computational load of our approach remains tractable, and therefore we are able to apply it to genome scale positive selection scans. We apply our new method to two datasets: 767 vertebrate orthologs and 8,606 orthologs from twelve Drosophila species. Our new model is strongly favored by the data, and the support of the model increases with the amount of information. Moreover, it is able to capture signatures of nucleotide level selection acting on translation initiation and on splicing sites within the coding region. Finally, we show that rate variation is highest in the highly recombining regions, and we hypothesize that recombination and mutation rate variation, such as high CpG mutation rate, are the two main sources of nucleotide rate variation. Overall, rate variation in substitutions is an important feature to capture, both to detect positive selection and to understand gene evolution, and the approach that we propose allows to do this in genome-wide scans.

Convergent consequences of parthenogenesis on stick insect genomes

“…The branch-site model with rate variation at the DNA level ( 44 ) was run using the Godon software (https://bitbucket.org/Davydov/godon/, version 2020-02-17, option BSG --ncat 4). Each branch was tested iteratively, in one run per gene tree.…”

“…While there is accumulating evidence for this process in experimental evolution studies (e.g., ( 41 – 43 )), its impact on natural populations remains unclear ( 17 , 39 ). To compare the efficiency of positive selection in sexual and parthenogenetic Timema , we used a branch-site model on the gene trees (( 44 ), Methods). We compared the terminal branches leading to sexual or parthenogenetic species in one-to-one orthologous genes identified in at least three species pairs (SM Table 4), using a threshold of q < 0.05 to classify which terminal branches show evidence of positive selection.…”

The evolutionary history of manatees told by their mitogenomes

“…when natural selection is favoring amino acid changes. We used the branch-site test for positive selection 40 implemented in Godon software 41 , which incorporate codon rate variation approaches, and gamma variation between codons [41][42][43] . We applied this test on the thirteen coding genes of Trichechus species and the outgroups.…”

Integrated evolutionary and structural analysis reveals xenobiotics and pathogens as the major drivers of mammalian adaptation

“…Information about structural placement of residues can also help to address technical issues that have hindered methods for detecting positive selection. Criticisms levelled at methods for detecting positive selection have revolved around the non-neutrality of synonymous substitutions, local variation in synonymous substitution rate [75][76][77][78] and the influence of errors in alignment 79,80 . These phenomena may cause false positives in parts of a protein sequence, but none will result in clustering on protein structure.…”