Jason N. Pitt

SEWAL: an open-source platform for next-generation sequence analysis and visualization

Next-generation DNA sequencing platforms provide exciting new possibilities for in vitro genetic analysis of functional nucleic acids. However, the size of the resulting data sets presents computational and analytical challenges. We present an open-source software package that employs a locality-sensitive hashing algorithm to enumerate all unique sequences in an entire Illumina sequencing run (∼108 sequences). The algorithm results in quasilinear time processing of entire Illumina lanes (∼107 sequences) on a desktop computer in minutes. To facilitate visual analysis of sequencing data, the software produces three-dimensional scatter plots similar in concept to Sewall Wright and John Maynard Smith’s adaptive or fitness landscape. The software also contains functions that are particularly useful for doped selections such as mutation frequency analysis, information content calculation, multivariate statistical functions (including principal component analysis), sequence distance metrics, sequence searches and sequence comparisons across multiple Illumina data sets. Source code, executable files and links to sample data sets are available at http://www.sourceforge.net/projects/sewal.

Rapamycin enhances survival in a Drosophila model of mitochondrial disease

Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS. However, the mechanism by which TOR inhibition exerts these effects, and the extent to which these effects can extend to other models of mitochondrial deficiency, are unknown. Here, we probe the effects of TOR inhibition in a Drosophila model of complex I deficiency. Treatment with rapamycin robustly suppresses the lifespan defect in this model of LS, without affecting behavioral phenotypes. Interestingly, this increased lifespan in response to TOR inhibition occurs in an autophagy-independent manner. Further, we identify a fat storage defect in the ND2 mutant flies that is rescued by rapamycin, supporting a model that rapamycin exerts its effects on mitochondrial disease in these animals by altering metabolism.

How RNA closes a Diel

The first structure of a ribozyme that catalyzes the stereospecific carbon-carbon bond formation between two small molecules shows how an RNA active site can perform the synthetically important Diels-Alder reaction. Surprisingly, the ribozyme active site shares structural features with proteins that catalyze the same reaction.

Correction: Why Is Aging Conserved and What Can We Do about it?

[This corrects the article DOI: 10.1371/journal.pbio.1002131.].

Inter-organ regulation of haem homeostasis

Haem is an iron-containing cofactor required for life. Many cellular processes rely on haem and failure to maintain iron homeostasis results in numerous pathological conditions. A study now identifies a Caenorhabditis elegans inter-organ signalling pathway in which secreted intestinal HRG-7 and neuronally secreted BMP signals coordinate animal haem homeostasis.