De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.     

Creatine accelerates the circadian clock in a unicellular alga

The circadian clock is considered to be a universal feature of eucaryotic organisms, controlling the occurrence and rates of many different aspects of life, ranging from single enzymatic reactions and metabolism to complex behaviours such as activity and rest. Although the nature of the underlying cellular/biochemical oscillator is still unknown, many substances are known to influence either phase or period of circadian rhythms in different organisms. These include D2O, electrolytes and ion channel inhibitors, small organic molecules such as alcohols and aldehydes, inhibitors of protein synthesis and amino-acid analogues. Certain transmitter and neurochemical drugs also influence the circadian clock in higher animals. We report here that the period of free-running circadian rhythms in the unicellular marine alga Gonyaulax polyedra is shortened by extracts from mammalian cells. The effect is dose-dependent, accelerating the circadian clock by as much as 4 hours per day. The substance responsible for this effect has been isolated from bovine muscle and identified as creatine. Authentic creatine has identical biological effects at micromolar concentrations and is known in animal systems for its involvement in cellular energy metabolism. A period shortening substance with similar chemical properties is also present in extracts of Gonyaulax itself.     

Non-responsiveness to a foot-and-mouth disease virus peptide overcome by addition of foreign helper T-cell determinants

Study of the immune response to synthetic antigens has shown that uncoupled peptides can realize their potential as vaccines only if they contain domains that react with helper T-cell receptors and Ia antigens in addition to antibody binding sites. Here we consider whether genetically restricted non-responsiveness to an uncoupled peptide could be overcome by synthesizing a peptide with an additional helper T-cell epitope from a different protein. We demonstrate that H-2d mice, which are non-responders to the 141-160 VP1 peptide of foot-and-mouth disease virus (FMDV), can be converted into responders by immunization with peptides containing the FMDV sequence with defined 'foreign' helper T-cell determinants from ovalbumin or sperm whale myoglobin. Furthermore, the virus-neutralizing activity of the antibody raised against peptide was dependent on the determinant used. Thus, FMDV peptides with the added sequences 323-339 from ovalbumin and 132-148 from sperm-whale myoglobin elicited a high degree of neutralizing activity in B10.D2 mice. The sera from mice which received the peptide with the added sequence 105-121 from sperm whale myoglobin did not neutralize the virus, although they had high levels of anti-141-160 FMDV peptide activity. Our data indicate that the T-cell help given by the 'foreign' epitopes is B-cell clone specific. These results are likely to have important implications for the design of peptide vaccines.     

Strong effect of dispersal network structure on ecological dynamics

A central question in ecology with great importance for management, conservation and biological control is how changing connectivity affects the persistence and dynamics of interacting species. Researchers in many disciplines have used large systems of coupled oscillators to model the behaviour of a diverse array of fluctuating systems in nature. In the well-studied regime of weak coupling, synchronization is favoured by increases in coupling strength and large-scale network structures (for example 'small worlds') that produce short cuts and clustering. Here we show that, by contrast, randomizing the structure of dispersal networks in a model of predators and prey tends to favour asynchrony and prolonged transient dynamics, with resulting effects on the amplitudes of population fluctuations. Our results focus on synchronization and dynamics of clusters in models, and on timescales, more appropriate for ecology, namely smaller systems with strong interactions outside the weak-coupling regime, rather than the better-studied cases of large, weakly coupled systems. In these smaller systems, the dynamics of transients and the effects of changes in connectivity can be well understood using a set of methods including numerical reconstructions of phase dynamics, examinations of cluster formation and the consideration of important aspects of cyclic dynamics, such as amplitude.     

Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat-mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.