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Additional file 3: Table S2. Shortlist of three candidate variants identified as plausible disease-causing variants.

Additional file 4: Table S3. Details of the candidate variant narrowed down using consecutive filters based on an autosomal recessive model of inheritance and low frequency.

Additional file 2: Table S1. Summary of exome sequencing data for the patient and his parents.

Additional file 1: Figure S1. Timeline of symptoms presented by the index case.

Each panel shows individuals plotted by sequential combinations of the first five principle components, color-coded by sample herd. Here we see no obvious clustering based on herd membership. The eigenvalues of the first twenty principle components are plotted as an inset in the top left panel with the first five PCs highlighted in red. We see the decrease in eigenvalue levels off after principle component five.;Animals heterozygous or homozygous for the ‘G’ risk allele (red or violet) produce 45% less IL-12 than CC animals following pokeweed mitogen stimulation of whole blood (top panel). IL-12 production was not significantly associated with variation at SNP3195. Additionally, we observed no detectable difference in interferon gamma (INFγ) or interleukin 4 (IL-4) production relative to SNP2253 and SNP3195 genotype in this herd.

Each panel shows individuals plotted by sequential combinations of the first five principle components, color-coded by sample herd. Here we see no obvious clustering based on herd membership. The eigenvalues of the first twenty principle components are plotted as an inset in the top left panel with the first five PCs highlighted in red. We see the decrease in eigenvalue levels off after principle component five.;Animals heterozygous or homozygous for the ‘G’ risk allele (red or violet) produce 45% less IL-12 than CC animals following pokeweed mitogen stimulation of whole blood (top panel). IL-12 production was not significantly associated with variation at SNP3195. Additionally, we observed no detectable difference in interferon gamma (INFγ) or interleukin 4 (IL-4) production relative to SNP2253 and SNP3195 genotype in this herd.

BACKGROUND: Tuberculosis, which is caused by Mycobacterium tuberculosis, remains one of the leading causes of mortality worldwide. The C-type lectin DC-SIGN is known to be the major M. tuberculosis receptor on human dendritic cells. We reasoned that if DC-SIGN interacts with M. tuberculosis, as well as with other pathogens, variation in this gene might have a broad range of influence in the pathogenesis of a number of infectious diseases, including tuberculosis. METHODS AND FINDINGS: We tested whether polymorphisms in CD209, the gene encoding DC-SIGN, are associated with susceptibility to tuberculosis through sequencing and genotyping analyses in a South African cohort. After exclusion of significant population stratification in our cohort, we observed an association between two CD209 promoter variants (-871G and -336A) and decreased risk of developing tuberculosis. By looking at the geographical distribution of these variants, we observed that their allelic combination is mainly confined to Eurasian populations. CONCLUSIONS: Our observations suggest that the two -871G and -336A variants confer protection against tuberculosis. In addition, the geographic distribution of these two alleles, together with their phylogenetic status, suggest that they may have increased in frequency in non-African populations as a result of host genetic adaptation to a longer history of exposure to tuberculosis. Further characterization of the biological consequences of DC-SIGN variation in tuberculosis will be crucial to better appreciate the role of this lectin in interactions between the host immune system and the tubercle bacillus as well as other pathogens.