GenomegaMap: Within-Species Genome-Wide dN/dS Estimation from over 10,000 Genomes

Abstract

The dN/dS ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters, such as dN/dS, but analyzing very large data sets poses a major statistical challenge. Here, I introduce genomegaMap for estimating within-species genome-wide variation in dN/dS, and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: 1) It is fast no matter how large the sample size and 2) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well estimated even when genomegaMap’s simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in Mycobacterium tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species.

Insertion and deletion evolution reflects antibiotics selection pressure in a Mycobacterium tuberculosis outbreak

“…We note that the inference of positive selection can only be performed for three of the 34 genes with parsimony informative indels due to the lack of SNPs in the remaining genes. We further discovered that four genes with parsimony informative indels (11.8%) are included in a set of 116 (3%) genes that were found to be under positive selection in a recent survey of dN/dS in MTB [36]. Thus, while indels can be found in genes that are under positive selection as calculated by the dN/dS ratio, they might also uncover additional genes involved in adaptation.…”

A 500-year tale of co-evolution, adaptation, and virulence: Helicobacter pylori in the Americas

“…MCMC was run twice for each analysis with 1000,000 iterations and a burn-in of 22,000 iterations. Both runs were compared for convergence at several parameters and merged to obtain distributions; graphs of omega data were produced using R [33]. Differences in positions under positive selection between American and non-American strains were compared using the MCMC output from the previous analyses.…”

Global surveillance of potential antiviral drug resistance in SARS-CoV-2: proof of concept focussing on the RNA-dependent RNA polymerase

“…Further, we inferred the ratio of nonsynonymous to synonymous mutations (dN/dS or omega) in a Bayesian sliding window approach using genomegamap 39 . We ran 1,000,000 MCMC chains with 100,000 as burn-ins.…”

“…A balance of non-synonymous and synonymous mutations (dN/dS = 1) is understood as neutral selection. We set the priors of theta (the observed nucleotide diversity of the sample population) to 0.0006 and for kappa (per-path rate bias, from which the transition/transversion ratio can be calculated as kappa/2) to 2.3 as previously inferred in Wilson (2020) 39 .…”