ALBERT

Description: The adaptor protein-2 sigma subunit (AP22) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP22 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca 2+ o ) homeostasis. To elucidate the role of AP22 in Ca 2+ o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP22 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP22 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP22 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP22 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa x sMg/100 x CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP22 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Description: TCGA's RNASeq data represent one of the largest collections of cancer transcriptomes ever assembled. RNASeq technology, combined with computational tools like our SpliceSeq package, provides a comprehensive, detailed view of alternative mRNA splicing. Aberrant splicing patterns in cancers have been implicated in such processes as carcinogenesis, de-differentiation and metastasis. TCGA SpliceSeq ( http://bioinformatics.mdanderson.org/TCGASpliceSeq ) is a web-based resource that provides a quick, user-friendly, highly visual interface for exploring the alternative splicing patterns of TCGA tumors. Percent Spliced In (PSI) values for splice events on samples from 33 different tumor types, including available adjacent normal samples, have been loaded into TCGA SpliceSeq. Investigators can interrogate genes of interest, search for the genes that show the strongest variation between or among selected tumor types, or explore splicing pattern changes between tumor and adjacent normal samples. The interface presents intuitive graphical representations of splicing patterns, read counts and various statistical summaries, including percent spliced in. Splicing data can also be downloaded for inclusion in integrative analyses. TCGA SpliceSeq is freely available for academic, government or commercial use.

Description: Current theories cannot explain how trans-Neptunian objects (TNOs) either formed in situ or how ultrawide trans-Neptunian binaries (TNBs) exist if they were formed closer to the Sun and were later dispersed during Neptune's migration. Furthermore, no theory can adequately explain the documented clustering of near 0° for TNOs with a  〉 150 au. Here, we show that not only is clustered for the nine long-period TNOs (LPTNOs) with a  〉 200 au, but is also grouped almost as closely. Neither of these orbital elements is randomly distributed for any collection of TNOs investigated, including those that are not in resonance with Neptune, those with q  〉 30 au, q  〉 44 au, and LPTNOs. Every frequency distribution of and indicates that many TNOs were recently affected by Neptune. Based on this study, we propose that TNOs were inside Neptune's orbit in the last few Myr. The TNOs then migrated outwards in a relatively short time period. Ultrawide TNBs never came close to Neptune during this migration, allowing these fragile pairs to remain intact. However, many other TNOs were perturbed as they passed Neptune, resulting in the distribution of orbital elements we see today for all TNOs, including those in the Kuiper belt and the LPTNOs.

Description: Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2 -encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs . In vitro , we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo , immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.

Description: Geographical variation among contiguous populations is frequently attributed to ecological divergence or historical isolation followed by secondary contact. Distinguishing between these effects is key to studies of incipient speciation and could be revealed by different genomic signatures. We used RAD-seq analyses to examine morphologically divergent populations of the endemic lizard ( Gallotia galloti ) from the volcanic island of Tenerife. Previous analyses have suggested ecological and historical causes to explain the morphological diversity. Analyses of 276,483 single nucleotide polymorphisms (SNPs) from 〉20 Mbp of the genome revealed one genetically divergent population from Anaga, a region associated with divergent mtDNA lineages in other Tenerife endemics. This population also has a high number of private alleles, and its divergence can be explained by historical isolation. Bayesian outlier analyses identified a small proportion of SNPs as candidates for selection (0.04%) which were strongly differentiated between xeric and mesic habitat types. Individual testing for specific xeric–mesic selection using an alternative approach also supported ecological divergence in a similarly small proportion of SNPs. The study indicates the roles of both historical isolation and ecological divergence in shaping genomic diversity in G. galloti . However, north–south morphological divergence appears solely associated with the latter and likely involves a relatively small proportion of the genome.

Description: Fermentation is a key process in many anaerobic environments. Varying the concentration of electron donor fed to a fermenting community is known to shift the distribution of products between hydrogen, fatty acids and alcohols. Work to date has focused mainly on the fermentation of glucose, and how the microbial community structure is affected has not been explored. We fed ethanol, lactate, glucose, sucrose or molasses at 100 me- eq. L –1 , 200 me- eq. L –1 or 400 me- eq. L –1 to batch-fed cultures with fermenting, methanogenic communities. In communities fed high concentrations of electron donor, the fraction of electrons channeled to methane decreased, from 34% to 6%, while the fraction of electrons channeled to short chain fatty acids increased, from 52% to 82%, averaged across all electron donors. Ethanol-fed cultures did not produce propionate, but did show an increase in electrons directed to acetate as initial ethanol concentration increased. In glucose, sucrose, molasses and lactate-fed cultures, propionate accumulation co-occurred with known propionate producing organisms. Overall, microbial communities were determined by the substrate provided, rather than its initial concentration, indicating that a change in community function, rather than community structure, is responsible for shifts in the fermentation products produced.

Description: We use multiple synthetic mitigation sea-level scenarios, together with a non-mitigation sea-level scenario from the Warming Acidification and Sea-level Projector model. We find sea-level rise continues to accelerate post 2100 for all but the most aggressive mitigation scenarios indicative of 1.5°C and 2.0°C. Using the Dynamic Interactive Vulnerability Assessment modelling framework, we project land and population exposed in the 1 in 100 year coastal flood plain under sea-level rise and population change. In 2000, the flood plain is estimated at 540 x10 3 km 2 . By 2100, under the mitigation scenarios, it ranges between 610 x10 3 km 2 and 640 x10 3 km 2 [580 x10 3 km 2 and 700 x10 3 km 2 for the 5 th and 95 th percentiles]. Thus differences between the mitigation scenarios are small in 2100. However, in 2300, flood plains are projected to increase to between 700 x10 3 km 2 and 960 x10 3 km 2 in 2300 [610 x10 3 km 2 and 1,290 x10 3 km 2 ] for the mitigation scenarios, but 1,630 x10 3 km 2 [1,190 x10 3 km 2 and 2,220 x10 3 km 2 ] for the non-mitigation scenario. The proportion of global population exposed to sea-level rise in 2300 is projected to be between 1.5% and 5.4% [1.2% to 7.6%] (assuming no population growth after 2100) for the aggressive mitigation and the non-mitigation scenario, respectively. Hence over centennial timescales there are significant benefits to climate change mitigation and temperature stabilization. However, sea-levels will continue to rise albeit at lower rates. Thus potential impacts will keep increasing necessitating adaptation to existing coastal infrastructure and the careful planning of new coastal developments.

Description: There are over 100 Be stars that are known to have neutron star companions but only one such system with a black hole. Previous theoretical work suggests that this is not due to their formation but due to the differences in X-ray luminosity. It has also been proposed that the truncation of the Be star’s circumstellar disc is dependent on the mass of the compact object. Hence, Be star discs in black hole binaries are smaller. Since accretion on to the compact object from the Be star’s disc is what powers the X-ray luminosity, a smaller disc in black hole systems leads to a lower luminosity. In this paper, simulations are performed with a range of eccentricities and compact object mass. The disc’s size and density are shown to be dependent on both quantities. Mass capture and, in turn, X-ray luminosity are heavily dependent on the size and density of the disc. Be/black hole binaries are expected to be up to ∼10 times fainter than Be/neutron star binaries when both systems have the same eccentricity and can be 100 times fainter when comparing systems with different eccentricity.

Description: Ocean island volcanoes erupt a wide range of magmatic compositions via a diverse range of eruptive styles. Understanding where and how these melts evolve is thus an essential component in the anticipation of future volcanic activity. Here we examine the role of crustal structure and magmatic flux in controlling the location, evolution and ultimately composition of melts at Ascension Island. Located in the South Atlantic, Ascension Island is an ocean island volcano that has produced a continuum of eruptive compositions from basalt to rhyolite in its 1 Myr subaerial eruptive history. Volcanic rocks broadly follow a silica-undersaturated subalkaline evolutionary trend, and new data presented here show a continuous compositional trend from basalt through trachyte to rhyolite. Detailed petrographic observations are combined with in situ geochemical analyses of crystals and glass, and new whole-rock major and trace element data from mafic and felsic pyroclastic and effusive deposits that span the entire range in eruptive ages and compositions found on Ascension Island. These data show that extensive fractional crystallization is the main driver for the production of felsic melts for Ascension Island, a volcano built on thin, young, oceanic crust. Strong spatial variations in the compositions of erupted magmas reveal the role of a heterogeneous lower crust; differing degrees of interaction with a zone of plutonic rocks are responsible for the range in mafic lava compositions, and for the formation of the central and eastern felsic complexes. A central core of nested, small-scale plutonic, or mush-like, bodies inhibits the ascent of mafic magmas, allowing sequential fractional crystallization within the lower crust, and generating felsic magmas in the core of the island. There is no evidence for magma mixing preserved in any of the studied eruptions, suggesting that magma storage regions are transient, and material is not recycled between eruptions.