Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

Common variants near MC4R are associated with fat mass, weight and risk of obesity

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.     

Deglacial rapid sea level rises caused by ice-sheet saddle collapses

The last deglaciation (21 to 7 thousand years ago) was punctuated by several abrupt meltwater pulses, which sometimes caused noticeable climate change. Around 14 thousand years ago, meltwater pulse 1A (MWP-1A), the largest of these events, produced a sea level rise of 14-18?metres over 350?years. Although this enormous surge of water certainly originated from retreating ice sheets, there is no consensus on the geographical source or underlying physical mechanisms governing the rapid sea level rise. Here we present an ice-sheet modelling simulation in which the separation of the Laurentide and Cordilleran ice sheets in North America produces a meltwater pulse corresponding to MWP-1A. Another meltwater pulse is produced when the Labrador and Baffin ice domes around Hudson Bay separate, which could be associated with the '8,200-year' event, the most pronounced abrupt climate event of the past nine thousand years. For both modelled pulses, the saddle between the two ice domes becomes subject to surface melting because of a general surface lowering caused by climate warming. The melting then rapidly accelerates as the saddle between the two domes gets lower, producing nine metres of sea level rise over 500 years. This mechanism of an ice 'saddle collapse' probably explains MWP-1A and the 8,200-year event and sheds light on the consequences of these events on climate.     

Field Life: Science in the American West During the Railroad Era

Historians generally assume that the geological theories of George Hoggart Toulmin (1754–1817) are identical to those of James Hutton. This paper seeks to establish that Toulmin's ideas are significantly distinct and possess an independent interest. It argues that Toulmin was highly exceptional in his treatment of the nature and history of Man within the discipline of geology, for he saw Man (like the Earth) as being eternal, and also treated Man totally naturalistically, as an integral, non-privileged part of the terraqueous system. The neglect of Toulmin by subsequent geologists is examined, and it is suggested that it was in part attributable to the unacceptability of his interpretation of Man.     

Sugar transporters for intercellular exchange and nutrition of pathogens

Sugar efflux transporters are essential for the maintenance of animal blood glucose levels, plant nectar production, and plant seed and pollen development. Despite broad biological importance, the identity of sugar efflux transporters has remained elusive. Using optical glucose sensors, we identified a new class of sugar transporters, named SWEETs, and show that at least six out of seventeen Arabidopsis, two out of over twenty rice and two out of seven homologues in Caenorhabditis elegans, and the single copy human protein, mediate glucose transport. Arabidopsis SWEET8 is essential for pollen viability, and the rice homologues SWEET11 and SWEET14 are specifically exploited by bacterial pathogens for virulence by means of direct binding of a bacterial effector to the SWEET promoter. Bacterial symbionts and fungal and bacterial pathogens induce the expression of different SWEET genes, indicating that the sugar efflux function of SWEET transporters is probably targeted by pathogens and symbionts for nutritional gain. The metazoan homologues may be involved in sugar efflux from intestinal, liver, epididymis and mammary cells.     

Malthus foiled again and again

Throughout history, increasing population has driven the need to increase agricultural efficiency, so averting successive 'malthusian' disasters. In the twentieth century, the application of scientific knowledge to agriculture yielded tremendous dividends, enabling cereal yields to increase threefold since 1950. But with the world's population projected to reach nine billion by the middle of this century, new ways must be found to increase yields while preserving natural habitats and biodiversity.