Four new species of Mesomyzostoma (Myzostomida: Annelida)

Mesomyzostoma Remscheid, 1918 currently includes three described species that live in the coelom and/or gonads of comatulid crinoids: Mesomyzostoma reichenspergeri Remscheid, 1918, Mesomyzostoma katoi Okada, 1933 and Mesomyzostoma lanterbecqae Summers and Rouse, 2014 in Summers, Al-Hakim et al. 2014. Here we describe four new species of Mesomyzostoma and assess their phylogenetic relationships using 18S rRNA, cytochrome oxidase subunit I and 16S rRNA sequence data. We also designate a neotype for M. katoi as the original types appear to be lost. We record M. reichenspergeri from the Australian Great Barrier Reef and from northern Papua New Guinea, but samples from the type locality (Aru Islands, Indonesia) and previously recorded host are needed for confirmation. The new species of Mesomyzostoma are one Japanese species: Mesomyzostoma okadai sp. nov., and three Australian species: Mesomyzostoma lobus sp. nov., Mesomyzostoma leukos sp. nov. and Mesomyzostoma botulus sp. nov. The first infects the coelom of crinoid arms and pinnules, and the other three are found in crinoid oral discs. We also record M. leukos sp. nov. and M. botulus sp. nov. from Papua New Guinea. Phylogenetic analyses suggest that M. okadai sp. nov. is the sister group to all other Mesomyzostoma.     

Evolution Made to Order: Plant Breeding and Technological Innovation in Twentieth-Century America

The last charcoal iron blast furnace in the United States shut down in 1945. The most obvious reason for the extraordinary longevity of this industry was the almost unlimited supply of virgin timber in the United States. Although an obvious explanation, it is deceptive. The much more crucial reason for the longevity of the American charcoal iron industry was the technical difficulties involved in adapting coke- and coal-smelted iron to existing industrial processes. Until these technological problems could be overcome, charcoal iron was able to preserve a place for itself in the industrial environment of the late 19th and early 20th centuries. By concentrating their attention on the rapid advance of coke-smelted iron from 1870 onward, historians of the American iron industry have neglected this ability of the older iron technology to adapt to the new industrial conditions.     

Recombination rates in admixed individuals identified by ancestry-based inference

Studies of recombination and how it varies depend crucially on accurate recombination maps. We propose a new approach for constructing high-resolution maps of relative recombination rates based on the observation of ancestry switch points among admixed individuals. We show the utility of this approach using simulations and by applying it to SNP genotype data from a sample of 2,565 African Americans and 299 African Caribbeans and detecting several hundred thousand recombination events. Comparison of the inferred map with high-resolution maps from non-admixed populations provides evidence of fine-scale differentiation in recombination rates between populations. Overall, the admixed map is well predicted by the average proportion of admixture and the recombination rate estimates from the source populations. The exceptions to this are in areas surrounding known large chromosomal structural variants, specifically inversions. These results suggest that outside of structurally variable regions, admixture does not substantially disrupt the factors controlling recombination rates in humans.     

Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10(-10)) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.     

Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)).     

Automating resequencing-based detection of insertion-deletion polymorphisms

Structural and insertion-deletion (indel) variants have received considerable recent attention, partly because of their phenotypic consequences. Among these variants, the most common are small indels ( approximately 1-30 bp). Identifying and genotyping indels using sequence traces obtained from diploid samples requires extensive manual review, which makes large-scale studies inconvenient. We report a new algorithm, implemented in available software (PolyPhred version 6.0), to help automate detection and genotyping of indels from sequence traces. The algorithm identifies heterozygous individuals, which permits the discovery of low-frequency indels. It finds 80% of all indel polymorphisms with almost no false positives and finds 97% with a false discovery rate of 10%. Additionally, genotyping accuracy exceeds 99%, and it correctly infers indel length in 96% of the cases. Using this approach, we identify indels in the HapMap ENCODE regions, providing the first report of these polymorphisms in this data set.     

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.     

The dynamic disulphide relay of quiescin sulphydryl oxidase

Protein stability, assembly, localization and regulation often depend on the formation of disulphide crosslinks between cysteine side chains. Enzymes known as sulphydryl oxidases catalyse de novo disulphide formation and initiate intra- and intermolecular dithiol/disulphide relays to deliver the disulphides to substrate proteins. Quiescin sulphydryl oxidase (QSOX) is a unique, multi-domain disulphide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention owing to its overproduction in tumours. In addition to its physiological importance, QSOX is a mechanistically intriguing enzyme, encompassing functions typically carried out by a series of proteins in other disulphide-formation pathways. How disulphides are relayed through the multiple redox-active sites of QSOX and whether there is a functional benefit to concatenating these sites on a single polypeptide are open questions. Here we present the first crystal structure of an intact QSOX enzyme, derived from a trypanosome parasite. Notably, sequential sites in the disulphide relay were found more than 40?? apart in this structure, too far for direct disulphide transfer. To resolve this puzzle, we trapped and crystallized an intermediate in the disulphide hand-off, which showed a 165° domain rotation relative to the original structure, bringing the two active sites within disulphide-bonding distance. The comparable structure of a mammalian QSOX enzyme, also presented here, shows further biochemical features that facilitate disulphide transfer in metazoan orthologues. Finally, we quantified the contribution of concatenation to QSOX activity, providing general lessons for the understanding of multi-domain enzymes and the design of new catalytic relays.