PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

A black hole in a globular cluster

Globular star clusters contain thousands to millions of old stars packed within a region only tens of light years across. Their high stellar densities make it very probable that their member stars will interact or collide. There has accordingly been considerable debate about whether black holes should exist in these star clusters. Some theoretical work suggests that dynamical processes in the densest inner regions of globular clusters may lead to the formation of black holes of approximately 1,000 solar masses. Other numerical simulations instead predict that stellar interactions will eject most or all of the black holes that form in globular clusters. Here we report the X-ray signature of an accreting black hole in a globular cluster associated with the giant elliptical galaxy NGC 4472 (in the Virgo cluster). This object has an X-ray luminosity of about 4 x 10(39) erg s(-1), which rules out any object other than a black hole in such an old stellar population. The X-ray luminosity varies by a factor of seven in a few hours, which excludes the possibility that the object is several neutron stars superposed.     

Ecology: global warming and amphibian losses

Is global warming contributing to amphibian declines and extinctions by promoting outbreaks of the chytrid fungus Batrachochytrium dendrobatidis? Analysing patterns from the American tropics, Pounds et al. envisage a process in which a single warm year triggers die-offs in a particular area (for instance, 1987 in the case of Monteverde, Costa Rica). However, we show here that populations of two frog species in the Australian tropics experienced increasing developmental instability, which is evidence of stress, at least two years before they showed chytrid-related declines. Because the working model of Pounds et al. is incomplete, their test of the climate-linked epidemic hypothesis could be inconclusive.     

CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.     

Aerobic bacterial pyrite oxidation and acid rock drainage during the Great Oxidation Event

The enrichment of redox-sensitive trace metals in ancient marine sedimentary rocks has been used to determine the timing of the oxidation of the Earth's land surface. Chromium (Cr) is among the emerging proxies for tracking the effects of atmospheric oxygenation on continental weathering; this is because its supply to the oceans is dominated by terrestrial processes that can be recorded in the Cr isotope composition of Precambrian iron formations. However, the factors controlling past and present seawater Cr isotope composition are poorly understood. Here we provide an independent and complementary record of marine Cr supply, in the form of Cr concentrations and authigenic enrichment in iron-rich sedimentary rocks. Our data suggest that Cr was largely immobile on land until around 2.48?Gyr ago, but within the 160?Myr that followed--and synchronous with independent evidence for oxygenation associated with the Great Oxidation Event (see, for example, refs 4-6)--marked excursions in Cr content and Cr/Ti ratios indicate that Cr was solubilized at a scale unrivalled in history. As Cr isotope fractionations at that time were muted, Cr must have been mobilized predominantly in reduced, Cr(III), form. We demonstrate that only the oxidation of an abundant and previously stable crustal pyrite reservoir by aerobic-respiring, chemolithoautotrophic bacteria could have generated the degree of acidity required to solubilize Cr(III) from ultramafic source rocks and residual soils. This profound shift in weathering regimes beginning at 2.48?Gyr ago constitutes the earliest known geochemical evidence for acidophilic aerobes and the resulting acid rock drainage, and accounts for independent evidence of an increased supply of dissolved sulphate and sulphide-hosted trace elements to the oceans around that time. Our model adds to amassing evidence that the Archaean-Palaeoproterozoic boundary was marked by a substantial shift in terrestrial geochemistry and biology.