Large-scale Pan Genomic Analysis of Mycobacterium tuberculosis Reveals Key Insights Into Molecular Evolutionary Rate of Specific Processes and Functions

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), an infectious disease that is a major killer worldwide. Due to selection pressure caused by the use of antibacterial drugs, Mtb is characterised by mutational events that have given rise to multi drug resistant (MDR) and extensively drug resistant (XDR) phenotypes. The rate at which mutations occur is an important factor in the study of molecular evolution, and it helps understand gene evolution. Within the same species, different protein-coding genes evolve at different rates. To estimate the rates of molecular evolution of protein-coding genes, a commonly used parameter is the ratio dN/dS, where dN is the rate of non-synonymous substitutions and dS is the rate of synonymous substitutions. Here, we determined the estimated rates of molecular evolution of select biological processes and molecular functions across 264 strains of Mtb. We also investigated the molecular evolutionary rates of core genes of Mtb by computing the dN/dS values, and estimated the pan genome of the 264 strains of Mtb. Our results show that the cellular amino acid metabolic process and the kinase activity function evolve at a significantly higher rate, while the carbohydrate metabolic process evolves at a significantly lower rate for M. tuberculosis. These high rates of evolution correlate well with Mtb physiology and pathogenicity. We further propose that the core genome of M. tuberculosis likely experiences varying rates of molecular evolution which may drive an interplay between core genome and accessory genome during M. tuberculosis evolution.

Keywords: Comparative genomics; Mycobacterium tuberculosis; dN/dS; molecular evolution.

Figure 1.

Box plots showing the distribution of dN/dS values for fast-evolving reference genes, slow-evolving reference genes, and genes of 3 biological processes of Mtb species, namely Cellular Amino Acid Metabolic Process (GO:0006520), Carbohydrate Metabolic Process (GO:0005975) and Cell Wall Organisation or Biogenesis (GO:0071554).

Figure 2.

Box plots showing distribution of dN/dS for fast-evolving reference genes, slow-evolving reference genes and genes of kinase activity (GO:0016301) and peptidase activity (GO:0008233) functions in the Mtb species.

Figure 3.

Box plots showing distribution of dN/dS for fast-evolving reference genes, slow-evolving reference genes and genes of transmembrane transporter functions (namely passive GO:0022803, active GO:0022804, inorganic molecular entity GO:0015318 and efflux GO:0015562) in the Mtb species.

Figure 4.

(A) Distribution of dN/dS values for different metabolic pathways in Mtb and (B) distribution of dN/dS values for different metabolic pathways of Mtb.

Figure 5.

The distribution of core (A), dispensable (B) and strain-specific (C) genes across 264 strains of Mtb.