Nature advance online publication 21 February 2010. doi:10.1038/nature08825

Authors: Jacques Fellay, Alexander J. Thompson, Dongliang Ge, Curtis E. Gumbs, Thomas J. Urban, Kevin V. Shianna, Latasha D. Little, Ping Qiu, Arthur H. Bertelsen, Mark Watson, Amelia Warner, Andrew J. Muir, Clifford Brass, Janice Albrecht, Mark Sulkowski, John G. McHutchison & David B. Goldstein

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

Nature advance online publication 24 February 2010. doi:10.1038/nature08826

Authors: Vicky A. Tobin, Hirofumi Hashimoto, Douglas W. Wacker, Yuki Takayanagi, Kristina Langnaese, Celine Caquineau, Julia Noack, Rainer Landgraf, Tatsushi Onaka, Gareth Leng, Simone L. Meddle, Mario Engelmann & Mike Ludwig

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader–Willi syndrome, affective disorders and obsessive–compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

Nature advance online publication 24 February 2010. doi:10.1038/nature08798

Authors: Steve Paterson, Tom Vogwill, Angus Buckling, Rebecca Benmayor, Andrew J. Spiers, Nicholas R. Thomson, Mike Quail, Frances Smith, Danielle Walker, Ben Libberton, Andrew Fenton, Neil Hall & Michael A. Brockhurst

The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation. Although the divergence observed at some host-resistance and parasite-infectivity genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Φ2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species.

Nature advance online publication 24 February 2010. doi:10.1038/nature08691

Authors: Margarita V. Meer, Alexey S. Kondrashov, Yael Artzy-Randrup & Fyodor A. Kondrashov

A long-standing controversy in evolutionary biology is whether or not evolving lineages can cross valleys on the fitness landscape that correspond to low-fitness genotypes, which can eventually enable them to reach isolated fitness peaks. Here we study the fitness landscapes traversed by switches between different AU and GC Watson–Crick nucleotide pairs at complementary sites of mitochondrial transfer RNA stem regions in 83 mammalian species. We find that such Watson–Crick switches occur 30–40 times more slowly than pairs of neutral substitutions, and that alleles corresponding to GU and AC non-Watson–Crick intermediate states segregate within human populations at low frequencies, similar to those of non-synonymous alleles. Substitutions leading to a Watson–Crick switch are strongly correlated, especially in mitochondrial tRNAs encoded on the GT-nucleotide-rich strand of the mitochondrial genome. Using these data we estimate that a typical Watson–Crick switch involves crossing a fitness valley of a depth of about 10-3 or even about 10-2, with AC intermediates being slightly more deleterious than GU intermediates. This compensatory evolution must proceed through rare intermediate variants that never reach fixation. The ubiquitous nature of compensatory evolution in mammalian mitochondrial tRNAs and other molecules implies that simultaneous fixation of two alleles that are individually deleterious may be a common phenomenon at the molecular level.

Nature advance online publication 28 February 2010. doi:10.1038/nature08843

Authors: Zachery R. Smith & Jeff A. Long

Plants, similarly to animals, form polarized axes during embryogenesis on which cell differentiation and organ patterning programs are orchestrated. During Arabidopsis embryogenesis, establishment of the shoot and root stem cell populations occurs at opposite ends of an apical–basal axis. Recent work has identified the PLETHORA (PLT) genes as master regulators of basal/root fate, whereas the master regulators of apical/shoot fate have remained elusive. Here we show that the PLT1 and PLT2 genes are direct targets of the transcriptional co-repressor TOPLESS (TPL) and that PLT1/2 are necessary for the homeotic conversion of shoots to roots in tpl-1 mutants. Using tpl-1 as a genetic tool, we identify the CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP III) transcription factors as master regulators of embryonic apical fate, and show they are sufficient to drive the conversion of the embryonic root pole into a second shoot pole. Furthermore, genetic and misexpression studies show an antagonistic relationship between the PLT and HD-ZIP III genes in specifying the root and shoot poles.