Desjardins, Christopher A.Cohen, Keira A.Munsamy, VanishaAbeel, ThomasMaharaj, KashmeelWalker, Bruce J.Shea, Terrance P.Almeida, Deepak V.Manson, Abigail L.Salazar, AlexPadayatchi, NesriO’Donnell, Max R.Mlisana, Koleka P.Wortman, JenniferBirren, Bruce W.Grosset, JacquesEarl, Ashlee M.Pym, Alexander S.2016-11-182016Desjardins, C. A., K. A. Cohen, V. Munsamy, T. Abeel, K. Maharaj, B. J. Walker, T. P. Shea, et al. 2016. “Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.” Nature genetics 48 (5): 544-551. doi:10.1038/ng.3548. http://dx.doi.org/10.1038/ng.3548.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408295A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss-of-function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss-of-function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted utilization of this toxic drug among patients with susceptible infections.en-USJournal Article2016-11-1810.1038/ng.3548