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A Practical Guide to Phylogenetics for Nonexperts

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Multiple Factors Confounding Phylogenetic Detection of Selection on Codon Usage.

Simon Laurin-Lemay¹, Hervé Philippe^1,2, Nicolas Rodrigue³

¹Department of Biochemistry and Molecular Medicine, Robert-Cedergren Center for Bioinformatics and Genomics, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.

Molecular Biology and Evolution

|March 30, 2018

Summary

The CUYN test for detecting selection on codon usage (CU) in mammals is highly susceptible to model violations, particularly CpG hypermutability, leading to frequent false positives. Careful evaluation of mutation models is crucial for accurate phylogenetic analysis.

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Area of Science:

Molecular Evolution
Genomics
Bioinformatics

Background:

Detecting selection on codon usage (CU) is challenging due to confounding factors like mutation bias and selective constraints.
The CUYN test, developed by Yang and Nielsen (2008), uses mutation-selection models to infer selection on CU.
Previous applications of CUYN on mammalian data suggested widespread selection on CU, which was unexpected given mammalian effective population sizes.

Purpose of the Study:

To evaluate the robustness of the CUYN test to model violations using simulations.
To investigate the impact of specific mutational processes, such as CpG hypermutability, on CUYN test results.
To assess the influence of different mutation parameterizations (e.g., HKY vs. GTR) on the test's performance.

Main Methods:

Simulations were conducted to mimic evolutionary processes under various conditions.
The CUYN test was applied to simulated data to assess its accuracy and identify sources of error.
Model violations, including CpG hypermutability and differing mutation parameterizations, were systematically introduced.

Main Results:

Simulations revealed that CpG hypermutability completely misled the CUYN test, resulting in 100% false positives.
Using HKY parameterization with GTR-simulated data led to a high false positive rate (56.1%).
CpG hypermutability was identified as a significant factor potentially explaining observed mammalian CU patterns.

Conclusions:

The CUYN test is not robust to violations of its underlying mutation-selection models.
CpG hypermutability is a critical factor that can generate false signals of selection on codon usage.
The study underscores the necessity of rigorously evaluating statistical tests in molecular phylogenetics for model misspecification.