Origin of avian genome size and structure in non-avian dinosaurs

Avian genomes are small and streamlined compared with those of other amniotes by virtue of having fewer repetitive elements and less non-coding DNA. This condition has been suggested to represent a key adaptation for flight in birds, by reducing the metabolic costs associated with having large genome and cell sizes. However, the evolution of genome architecture in birds, or any other lineage, is difficult to study because genomic information is often absent for long-extinct relatives. Here we use a novel bayesian comparative method to show that bone-cell size correlates well with genome size in extant vertebrates, and hence use this relationship to estimate the genome sizes of 31 species of extinct dinosaur, including several species of extinct birds. Our results indicate that the small genomes typically associated with avian flight evolved in the saurischian dinosaur lineage between 230 and 250 million years ago, long before this lineage gave rise to the first birds. By comparison, ornithischian dinosaurs are inferred to have had much larger genomes, which were probably typical for ancestral Dinosauria. Using comparative genomic data, we estimate that genome-wide interspersed mobile elements, a class of repetitive DNA, comprised 5-12% of the total genome size in the saurischian dinosaur lineage, but was 7-19% of total genome size in ornithischian dinosaurs, suggesting that repetitive elements became less active in the saurischian lineage. These genomic characteristics should be added to the list of attributes previously considered avian but now thought to have arisen in non-avian dinosaurs, such as feathers, pulmonary innovations, and parental care and nesting.     

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.     

Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome

Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.     

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Systemic Practice and Action Research -     

Lamellipodia mediate the heterogeneity of central olfactory ensheathing cell interactions

The growth and guidance of primary olfactory axons are partly attributed to the presence of olfactory ensheathing cells (OECs). However, little is understood about the differences between the subpopulations of OECs and what regulates their interactions. We used OEC-axon assays and determined that axons respond differently to peripheral and central OECs. We then further purified OECs from anatomically distinct regions of the olfactory bulb. Cell behaviour assays revealed that OECs from the olfactory bulb were a functionally heterogeneous population with distinct differences which is consistent with their proposed roles in vivo. We found that the heterogeneity was regulated by motile lamellipodial waves along the shaft of the OECs and that inhibition of lamellipodial wave activity via Mek1 abolished the ability of the cells to distinguish between each other. These results demonstrate that OECs from the olfactory bulb are a heterogeneous population that use lamellipodial waves to regulate cell–cell recognition.     

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.     

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16).     

A powerful bursting radio source towards the Galactic Centre

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. Although high-time-resolution observations are often possible in radio astronomy, they are usually limited to quite narrow fields of view. The dynamic radio sky is therefore poorly sampled, in contrast to the situation in the X-ray and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a transient radio source, GCRT J1745-3009, which was detected during a moderately wide-field monitoring programme of the Galactic Centre region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the Galactic Centre, its brightness temperature (approximately 10(16) K) and the implied energy density within GCRT J1745-3009 vastly exceed those observed in most other classes of radio astronomical sources, and are consistent with coherent emission processes that are rarely observed. We conclude that it represents a hitherto unknown class of transient radio sources, the first of possibly many new classes that may be discovered by emerging wide-field radio telescopes.     

Structure of C3b in complex with CRIg gives insights into regulation of complement activation

The complement system is a key part of the innate immune system, and is required for clearance of pathogens from the bloodstream. After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases. CRIg, a complement receptor expressed on macrophages, binds to C3b and iC3b mediating phagocytosis of the particles, but it is unknown how CRIg selectively recognizes proteolytic C3-fragments and whether binding of CRIg to C3b inhibits convertase activation. Here we present the crystal structure of C3b in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as an inhibitor of the alternative pathway of complement. The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (>80 A) of the thioester-bond-containing domain through which C3b attaches to pathogen surfaces. We show that CRIg is not only a phagocytic receptor, but also a potent inhibitor of the alternative pathway convertases. The structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition. Moreover, our structure-function studies relating the structural basis of complement activation and the means by which CRIg inhibits the convertases provide important clues to the development of therapeutics that target complement.