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.     

High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi

Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers.     

γ-Aminobutyric acid (GABA) signalling in plants

The role of γ-aminobutyric acid (GABA) as a signal in animals has been documented for over 60 years. In contrast, evidence that GABA is a signal in plants has only emerged in the last 15 years, and it was not until last year that a mechanism by which this could occur was identified—a plant ‘GABA receptor’ that inhibits anion passage through the aluminium-activated malate transporter family of proteins (ALMTs). ALMTs are multigenic, expressed in different organs and present on different membranes. We propose GABA regulation of ALMT activity could function as a signal that modulates plant growth, development, and stress response. In this review, we compare and contrast the plant ‘GABA receptor’ with mammalian GABA_A receptors in terms of their molecular identity, predicted topology, mode of action, and signalling roles. We also explore the implications of the discovery that GABA modulates anion flux in plants, its role in signal transduction for the regulation of plant physiology, and predict the possibility that there are other GABA interaction sites in the N termini of ALMT proteins through in silico evolutionary coupling analysis; we also explore the potential interactions between GABA and other signalling molecules.     

Gastrointestinal helminths of nine species of Cnemaspis (Squamata: Gekkonidae) from Peninsular Malaysia,one species from Cambodia and Thailand and two species from Vietnam

A total of 12 species of Cnemaspis (N = 104) from Southeast Asia were examined for gastrointestinal helminths. Samples consisted of nine species (n = 86) from Peninsular Malaysia: Cnemaspis affinis (n = 4); Cnemaspis baueri (n = 17); Cnemaspis biocellata (n = 12); Cnemaspis grismeri (n = 8); Cnemaspis kumpoli (n = 11); Cnemaspis limi (n = 9): Cnemaspis monachorum (n = 7); Cnemaspis pemanggilensis (n = 10); Cnemaspis peninsularis (n = 8); one species (n = 5) from Cambodia and Thailand, Cnemaspis chanthaburiensis (n = 5); and two species (n = 13) from Vietnam: Cnemaspis nuicamensis (n = 6) and Cnemaspis tucdupensis (n = 7). The aggregate helminth community consisted of one species of Cestoda, Cylindrotaenia malayi and nine species of Nematoda: Bakeria schadi, Meteterakis singaporensis, Parapharyngodon maplestoni, Maxvachonia sp., Physalopteroides sp., Physalopteridae gen. sp., Riticulariidae gen. sp., Seuratoidea gen. sp., Ascaridoidea gen. sp. Meteterakis singaporensis had the largest number of individuals (457) and greatest prevalence (24%). Twenty-eight new host records are reported.     

On the Difficulty of Measuring Forecasting Skill in Financial Markets

The use of correlation between forecasts and actual returns is commonplace in the literature, often used as a measurement of investors' skill. A prominent application of this is the concept of the information coefficient (IC). Not only can the IC be used as a tool to rate analysts and fund managers but it also represents an important parameter in the asset allocation and portfolio construction process. Nevertheless, a theoretical understanding of it has typically been limited to the partial equilibrium context where the investing activities of each agent have no effect on other market participants. In this paper we show that this can be an undesirable oversimplification and we demonstrate plausible circumstances in which conventional empirical measurements of IC can be highly misleading. We suggest that improved understanding of IC in a general equilibrium setting can lead to refined portfolio decision making ex ante and more informative analysis of performance ex post. Copyright © 2015 John Wiley & Sons, Ltd.     

CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.     

Genome-wide recombination in Chlamydia trachomatis

A new study reports comparative genomic analysis of 52 geographically diverse strains of Chlamydia trachomatis. The authors reconstruct a genome-wide phylogeny of the species and report extensive genome-wide recombination across multiple lineages of this intracellular bacterial pathogen.     

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

The goal of explanation

I defend the claim that understanding is the goal of explanation against various persistent criticisms, especially the criticism that understanding is not truth-connected in the appropriate way, and hence is a merely psychological (rather than epistemic) state. Part of the reason why understanding has been dismissed as the goal of explanation, I suggest, is because the psychological dimension of the goal of explanation has itself been almost entirely neglected. In turn, the psychological dimension of understanding—the Aha! experience, the sense that a certain explanation “feels right”, and so on—has been conspicuously overemphasized. I try to correct for both of these exaggerations. Just as the goal of explanation includes a richer psychological—including phenomenological—dimension than is generally acknowledged, so too understanding has a stronger truth connection than is generally acknowledged.