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Fine-scale evolution of Mycobacterium tuberculosis growth rate

K M Malone(1,2) L Lima(1) J Knaggs(1,2) M Hunt(1,2) P Fowler(2) D Crooke(2) Z Iqbal(1)

1:EMBL-EBI; 2:University of Oxford

Understanding how modest genomic diversity amongst the Mycobacterium tuberculosis lineages influences fitness is vital for devising successful tuberculosis control strategies. Growth rate is intimately linked to fitness and to date, only a handful of studies have identified variation in growth rate between particular lineages in vitro. Here, we describe the evolution of growth rate across a phylogeny of over 10,000 clinical isolates representing major lineages 1-4 from 23 different countries. We find that the entire phylogeny can be divided into 11 different clades based on growth rate. Ancestral sequence reconstruction highlights genetic changes associated with growth rate that have become fixed in the emergence of specific sub-lineages prior to the introduction of antibiotics. Alteration to growth rate appears to have evolved independently amongst the clades with differences in metabolic pathways having a more significant impact on growth than convergent evolution in a specific set of genes. Finally, we demonstrate the usefulness of our clade classification for exploration of additional phenotypes by showcasing the impact of variation at codon 306 of embB on the minimum inhibitory concentration of ethambutol and how genetic prediction of resistance to this drug should take account of sub-lineage. 

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