A Novel Test for Gene-Ancestry Interactions in Genome-Wide Association Data

Genome-wide association study (GWAS) data on a disease are increasingly available from multiple related populations. In this scenario, meta-analyses can improve power to detect homogeneous genetic associations, but if there exist ancestry-specific effects, via interactions on genetic background or with a causal effect that co-varies with genetic background, then these will typically be obscured. To address this issue, we have developed a robust statistical method for detecting susceptibility gene-ancestry interactions in multi-cohort GWAS based on closely-related populations. We use the leading principal components of the empirical genotype matrix to cluster individuals into “ancestry groups” and then look for evidence of heterogeneous genetic associations with disease or other trait across these clusters. Robustness is improved when there are multiple cohorts, as the signal from true gene-ancestry interactions can then be distinguished from gene-collection artefacts by comparing the observed interaction effect sizes in collection groups relative to ancestry groups. When applied to colorectal cancer, we identified a missense polymorphism in iron-absorption gene CYBRD1 that associated with disease in individuals of English, but not Scottish, ancestry. The association replicated in two additional, independently-collected data sets. Our method can be used to detect associations between genetic variants and disease that have been obscured by population genetic heterogeneity. It can be readily extended to the identification of genetic interactions on other covariates such as measured environmental exposures. We envisage our methodology being of particular interest to researchers with existing GWAS data, as ancestry groups can be easily defined and thus tested for interactions.     

Developmental biology: a growing role for computer simulations

Keeping cells separated in well-defined domains is essential for development. A new computational-experimental study elucidates the physical mechanisms that establish and maintain the dorsal-ventral compartment boundary in the Drosophila wing disc and demonstrates the increasing value of computer simulations in developmental biology.     

Variation of scavenger richness and abundance between sites of high and low iceberg scour frequency in Ryder Bay,west Antarctic Peninsula

Physical disturbance, particularly from iceberg scour, is a major structuring force in polar benthic communities at shelf depths. Scouring kills and damages benthic organisms providing food for the abundant scavenging fauna of coastal Antarctic waters. This trophic group is likely to be strongly affected by changes in iceberg scouring. A baited underwater camera system was used to examine the distribution of scavenging fauna in relation to the spatial variation in exposure to iceberg impacts experienced at different iceberg scouring conditions and depths within Ryder Bay. The results indicate that the relationships between depth and scavenger abundance and assemblage composition differed between high and low scour sites. Scavenger abundance increased with depth at high scour sites and fell with depth a low scour sites. There was also significant difference in community composition between sites within each scouring condition. Scavenger species richness also exhibited an increase with depth at most sites consistent with the established pattern of declining iceberg scouring frequency with depth. Shannon–Wiener diversity increased with depth but significantly more steeply in highly scoured sites. Our results suggest that depth and exposure to icebergs interact to shape the scavenger community. The significant differences within the high and low scour groups suggest that other factors remain to be investigated and that there is probably a nonlinear relationship between scouring intensity and the favourability of a site for scavengers.     

Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons

Aggregate‐prone mutant proteins, such as α‐synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate‐prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL‐threo‐1‐Phenyl‐2‐palmitoylamino‐3‐morpholino‐1‐propanol and Genz‐123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT‐mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on‐target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α‐synuclein in neurons, it does so, according to our data, through autophagy‐independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease.

     

An assessment of biomass for bioelectricity and biofuel,and for greenhouse gas emission reduction in Australia

We provide a quantitative assessment of the prospects for current and future biomass feedstocks for bioenergy in Australia, and associated estimates of the greenhouse gas (GHG) mitigation resulting from their use for production of biofuels or bioelectricity. National statistics were used to estimate current annual production from agricultural and forest production systems. Crop residues were estimated from grain production and harvest index. Wood production statistics and spatial modelling of forest growth were used to estimate quantities of pulpwood, in‐forest residues, and wood processing residues. Possible new production systems for oil from algae and the oil‐seed tree Pongamia pinnata, and of lignocellulosic biomass production from short‐rotation coppiced eucalypt crops were also examined. The following constraints were applied to biomass production and use: avoiding clearing of native vegetation; minimizing impacts on domestic food security; retaining a portion of agricultural and forest residues to protect soil; and minimizing the impact on local processing industries by diverting only the export fraction of grains or pulpwood to bioenergy. We estimated that it would be physically possible to produce 9.6 GL yr^?1 of first generation ethanol from current production systems, replacing 6.5 GL yr^?1 of gasoline or 34% of current gasoline usage. Current production systems for waste oil, tallow and canola seed could produce 0.9 GL yr^?1 of biodiesel, or 4% of current diesel usage. Cellulosic biomass from current agricultural and forestry production systems (including biomass from hardwood plantations maturing by 2030) could produce 9.5 GL yr^?1 of ethanol, replacing 6.4 GL yr^?1 of gasoline, or ca. 34% of current consumption. The same lignocellulosic sources could instead provide 35 TWh yr^?1, or ca. 15% of current electricity production. New production systems using algae and P. pinnata could produce ca. 3.96 and 0.9 GL biodiesel yr^?1, respectively. In combination, they could replace 4.2 GL yr^?1 of fossil diesel, or 23% of current usage. Short‐rotation coppiced eucalypt crops could provide 4.3 GL yr^?1 of ethanol (2.9 GL yr^?1 replacement, or 15% of current gasoline use) or 20.2 TWh yr^?1 of electricity (9% of current generation). In total, first and second generation fuels from current and new production systems could mitigate 26 Mt CO₂‐e, which is 38% of road transport emissions and 5% of the national emissions. Second generation fuels from current and new production systems could mitigate 13 Mt CO₂‐e, which is 19% of road transport emissions and 2.4% of the national emissions lignocellulose from current and new production systems could mitigate 48 Mt CO₂‐e, which is 28% of electricity emissions and 9% of the national emissions. There are challenging sustainability issues to consider in the production of large amounts of feedstock for bioenergy in Australia. Bioenergy production can have either positive or negative impacts. Although only the export fraction of grains and sugar was used to estimate first generation biofuels so that domestic food security was not affected, it would have an impact on food supply elsewhere. Environmental impacts on soil, water and biodiversity can be significant because of the large land base involved, and the likely use of intensive harvest regimes. These require careful management. Social impacts could be significant if there were to be large‐scale change in land use or management. In addition, although the economic considerations of feedstock production were not covered in this article, they will be the ultimate drivers of industry development. They are uncertain and are highly dependent on government policies (e.g. the price on carbon, GHG mitigation and renewable energy targets, mandates for renewable fuels), the price of fossil oil, and the scale of the industry.     

Your attention please: increasing ambient noise levels elicits a change in communication behaviour in humpback whales (Megaptera novaeangliae)

High background noise is an important obstacle in successful signal detection and perception of an intended acoustic signal. To overcome this problem, many animals modify their acoustic signal by increasing the repetition rate, duration, amplitude or frequency range of the signal. An alternative method to ensure successful signal reception, yet to be tested in animals, involves the use of two different types of signal, where one signal type may enhance the other in periods of high background noise. Humpback whale communication signals comprise two different types: vocal signals, and surface-generated signals such as ‘breaching’ or ‘pectoral slapping’. We found that humpback whales gradually switched from primarily vocal to primarily surface-generated communication in increasing wind speeds and background noise levels, though kept both signal types in their repertoire. Vocal signals have the advantage of having higher information content but may have the disadvantage of loosing this information in a noisy environment. Surface-generated sounds have energy distributed over a greater frequency range and may be less likely to become confused in periods of high wind-generated noise but have less information content when compared with vocal sounds. Therefore, surface-generated sounds may improve detection or enhance the perception of vocal signals in a noisy environment.     

Enhanced glucose-induced insulin release and endogenous Ca2+ ionophoretic activity in neonatal rat islets following islet-activating protein

Islet-Activating Protein, purified from the culture medium of Bordetella pertussis, enhanced glucose-induced insulin secretion from cultured neonatal rat islets in a calcium dependent manner. This effect was accompanied by an increase in lipid associated Ca2+ ionophoretic activity, as measured by passage of Ca2+ through multilamellar planar membranes containing islet lipid extracts. These findings suggest that the action of IAP in the neonatal islet may be mediated by enhanced entry of extracellular calcium following an effect on membrane lipid composition.     

Transient axonal side branches in the developing mammalian optic nerve

Optic axons were labelled with horseradish peroxidase to establish the presence of side branches and examine their distribution and morphology in the developing optic nerve of the quokka wallaby, Setonix brachyurus, the cat and rat at stages when axon numbers are at their peak. In each species, three quarters of the axons were essentially straight and lacked side branches. The remaining axons took significantly longer paths and bore side branches, mostly at points where axons undulated or changed direction. Side branches occurred at intervals of 28–43 µm, had lengths of 2–3 µm and were usually simple rather than branched. A minority (1%) of the axons crossed diagonally between fascicles and two thirds of these had more side branches (interval: 10–18 µm) on the interfascicular portion than were found on the forward-directed axons. A small number of axons (0.01%) doubled back to grow retrogradely towards the eye, these axons also bore relatively more side branches (interval: 8–22 µm), especially at points where the axons changed direction. Ultrastructural reconstruction showed that side branches resembled small axonal profiles and constituted 2% of the total axon number. It is suggested that side branches are involved in the fine-tuning of growth cone navigation. Most side branches are lost by adulthood, indicating their transient nature. The absence of retrogradely-directed axons from adults suggests that cells with such axons are removed by naturally occurring cell death.