Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum.

BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.

TissueInfo: high-throughput identification of tissue expression profiles and specificity.

We describe TissueInfo, a knowledge-based method for the high-throughput identification of tissue expression profiles and tissue specificity. TissueInfo defines a set of tissue information calculations that can be computed for large numbers of genes, expressed sequence tags (ESTs) or proteins. Tissue information records that result from the TissueInfo calculations are used to generate tables suitable for data mining and for the selection of genes according to a given expression profile or specificity. When benchmarked against a test set of 116 proteins and literature information, TissueInfo was found to be accurate for 69% of identified tissue specificities and for 80% of expression profiles. The accuracy of the identifications can be increased if query sequences for which little information is available from dbEST are ignored. Thus, with 80% coverage, TissueInfo achieves an accuracy of 76% for specificity and 89% for expression. For the same set of proteins, the curated tissue specificity offered in SWISS-PROT was accurate in 78% of cases. TissueInfo can be useful for the selection of clones for custom microarrays, selection of training sets for ab initio identification of tissue information, gene discovery and genome-wide predictions. Further information about the program can be found at http://icb.mssm.edu/tissueinfo.

Estimation of synteny conservation and genome compaction between pufferfish (Fugu) and human.

BACKGROUND: Knowledge of the amount of gene order and synteny conservation between two species gives insights to the extent and mechanisms of divergence. The vertebrate Fugu rubripes (pufferfish) has a small genome with little repetitive sequence which makes it attractive as a model genome. Genome compaction and synteny conservation between human and Fugu were studied using data from public databases. METHODS: Intron length and map positions of human and Fugu orthologues were compared to analyse relative genome compaction and synteny conservation respectively. The divergence of these two genomes by genome rearrangement was simulated and the results were compared to the real data. RESULTS: Analysis of 199 introns in 22 orthologous genes showed an eight-fold average size reduction in Fugu, consistent with the ratio of total genome sizes. There was no consistent pattern relating the size reduction in individual introns or genes to gene base composition in either species. For genes that are neighbours in Fugu (genes from the same cosmid or GenBank entry), 40-50% have conserved synteny with a human chromosome. This figure may be underestimated by as much as two-fold, due to problems caused by incomplete human genome sequence data and the existence of dispersed gene families. Some genes that are neighbours in Fugu have human orthologues that are several megabases and tens of genes apart. This is probably caused by small inversions or other intrachromosomal rearrangements. CONCLUSIONS: Comparison of observed data to computer simulations suggests that 4000-16 000 chromosomal rearrangements have occurred since Fugu and human shared a common ancestor, implying a faster rate of rearrangement than seen in human/mouse comparisons.

Eukaryote genome duplication - where's the evidence?

Several eukaryotes, including maize, yeast and Xenopus, are degenerate polyploids formed by relatively recent whole-genome duplications. Ohno's conjecture that more ancient genome duplications occurred in an ancestor of vertebrates is probably at least partly true but the present shortage of gene sequence and map information from vertebrates makes it difficult to either prove or disprove this hypothesis. Candidate paralogous segments in mammalian genomes have been identified but the lack of statistical rigour means that many of the proposals in the literature are probably artefacts.