Draft genome sequence of the thermoalkaliphilic Caldalkalibacillus thermarum strain TA2.A1.

The genes and molecular machines that allow for a thermoalkaliphilic lifestyle have not been defined. To address this goal, we report on the improved high-quality draft genome sequence of Caldalkalibacillus thermarum strain TA2.A1, an obligately aerobic bacterium that grows optimally at pH 9.5 and 65 to 70°C on a wide variety of carbon and energy sources.

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Control of the false discovery rate applied to the detection of positively selected amino acid sites.

In this article, we consider the probabilistic identification of amino acid positions that evolve under positive selection as a multiple hypothesis testing problem. The null hypothesis "H0,s: site s evolves under a negative selection or under a neutral process of evolution" is tested at each codon site of the alignment of homologous coding sequences. Standard hypothesis testing is based on the control of the expected proportion of falsely rejected null hypotheses or type-I error rate. As the number of tests increases, however, the power of an individual test may become unacceptably low. Recent advances in statistics have shown that the false discovery rate--in this case, the expected proportion of sites that do not evolve under positive selection among those that are estimated to evolve under this selection regime--is a quantity that can be controlled. Keeping the proportion of false positives low among the significant results generally leads to an increase in power. In this article, we show that controlling the false detection rate is relevant when searching for positively selected sites. We also compare this new approach to traditional methods using extensive simulations.