InterStoreDB:A Generic Integration Resource for Genetic and Genomic Data

Associating phenotypic traits and quantitative trait loci (QTL) to causative regions of the underlying genome is a key goal in agricultural research.InterStoreDB is a suite of integrated databases designed to assist in this process.The individual databases are species independent and generic in design,providing access to curated datasets relating to plant populations,phenotypic traits,genetic maps,marker loci and QTL,with links to functional gene annotation and genomic sequence data.Each component database provides access to associated metadata,including data provenance and parameters used in analyses,thus providing users with information to evaluate the relative worth of any associations identified.The databases include CropStoreDB,for management of population,genetic map,QTL and trait measurement data,SeqStoreDB for sequence-related data and AlignStoreDB,which stores sequence alignment information,and allows navigation between genetic and genomic datasets.Genetic maps are visualized and compared using the CMAP tool,and functional annotation from sequenced genomes is provided via an EnsEMBL-based genome browser.This framework facilitates navigation of the multiple biological domains involved in genetics and genomics research in a transparent manner within a single portal.We demonstrate the value of InterStoreDB as a tool for Brassica research.InterStoreDB is available from:http://www.interstoredb.org     

Quantitative trait loci for magnitude of the plasma cortisol response to confinement in rainbow trout

Better understanding of the mechanisms underlying interindividual variation in stress responses and their links with production traits is a key issue for sustainable animal breeding. In this study, we searched for quantitative trait loci (QTL) controlling the magnitude of the plasma cortisol stress response and compared them to body size traits in five F2 full‐sib families issued from two rainbow trout lines divergently selected for high or low post‐confinement plasma cortisol level. Approximately 1000 F2 individuals were individually tagged and exposed to two successive acute confinement challenges (1 month interval). Post‐stress plasma cortisol concentrations were determined for each fish. A medium density genome scan was carried out (268 markers, overall marker spacing less than 10 cM). QTL detection was performed using qtlmap software, based on an interval mapping method ( http://www.inra.fr/qtlmap ). Overall, QTL of medium individual effects on cortisol responsiveness (<10% of phenotypic variance) were detected on 18 chromosomes, strongly supporting the hypothesis that control of the trait is polygenic. Although a core array of QTL controlled cortisol concentrations at both challenges, several QTL seemed challenge specific, suggesting that responses to the first and to a subsequent exposure to the confinement stressor are distinct traits sharing only part of their genetic control. Chromosomal location of the steroidogenic acute regulatory protein (STAR) makes it a good potential candidate gene for one of the QTL. Finally, comparison of body size traits QTL (weight, length and body conformation) with cortisol‐associated QTL did not support evidence for negative genetic relationships between the two types of traits.     

R/qtl: high-throughput multiple QTL mapping

MOTIVATION: R/qtl is free and powerful software for mapping and exploring quantitative trait loci (QTL). R/qtl provides a fully comprehensive range of methods for a wide range of experimental cross types. We recently added multiple QTL mapping (MQM) to R/qtl. MQM adds higher statistical power to detect and disentangle the effects of multiple linked and unlinked QTL compared with many other methods. MQM for R/qtl adds many new features including improved handling of missing data, analysis of 10,000 s of molecular traits, permutation for determining significance thresholds for QTL and QTL hot spots, and visualizations for cis-trans and QTL interaction effects. MQM for R/qtl is the first free and open source implementation of MQM that is multi-platform, scalable and suitable for automated procedures and large genetical genomics datasets. AVAILABILITY: R/qtl is free and open source multi-platform software for the statistical language R, and is made available under the GPLv3 license. R/qtl can be installed from http://www.rqtl.org/. R/qtl queries should be directed at the mailing list, see http://www.rqtl.org/list/. CONTACT: kbroman@biostat.wisc.edu.     

Bayesian quantitative trait loci mapping for multiple traits

Most quantitative trait loci (QTL) mapping experiments typically collect phenotypic data on multiple correlated complex traits. However, there is a lack of a comprehensive genomewide mapping strategy for correlated traits in the literature. We develop Bayesian multiple-QTL mapping methods for correlated continuous traits using two multivariate models: one that assumes the same genetic model for all traits, the traditional multivariate model, and the other known as the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We develop computationally efficient Markov chain Monte Carlo (MCMC) algorithms for performing joint analysis. We conduct extensive simulation studies to assess the performance of the proposed methods and to compare with the conventional single-trait model. Our methods have been implemented in the freely available package R/qtlbim (http://www.qtlbim.org), which greatly facilitates the general usage of the Bayesian methodology for unraveling the genetic architecture of complex traits.     

Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Studies of BMD in families and twins have shown that this trait is under strong genetic control. To identify regions of the genome that contain quantitative trait loci (QTL) for BMD, we performed independent genomewide screens, using two complementary study designs. We analyzed unselected nonidentical twin pairs (1,094 pedigrees) and highly selected, extremely discordant or concordant (EDAC) sib pairs (254 pedigrees). Nonparametric multipoint linkage (NPL) analyses were undertaken for lumbar spine and total-hip BMD in both cohorts and for whole-body BMD in the unselected twin pairs. The maximum evidence of linkage in the unselected twins (spine BMD, LOD 2.7) and the EDAC pedigrees (spine BMD, LOD 2.1) was observed at chromosome 3p21 (76 cM and 69 cM, respectively). These combined data indicate the presence, in this region, of a gene that regulates BMD. Furthermore, evidence of linkage in the twin cohort (whole-body BMD; LOD 2.4) at chromosome 1p36 (17 cM) supports previous findings of suggestive linkage to BMD in the region. Weaker evidence of linkage (LOD 1.0-2.3) in either cohort, but not both, indicates the locality of additional QTLs. These studies validate the use, in linkage analysis, of large cohorts of unselected twins phenotyped for multiple traits, and they highlight the importance of conducting genome scans in replicate populations as a prelude to positional cloning and gene discovery.     

Multiple-interval mapping for quantitative trait loci controlling endosperm traits

Endosperm traits are trisomic inheritant and are of great economic importance because they are usually directly related to grain quality. Mapping for quantitative trait loci (QTL) underlying endosperm traits can provide an efficient way to genetically improve grain quality. As the traditional QTL mapping methods (diploid methods) are usually designed for traits under diploid control, they are not the ideal approaches to map endosperm traits because they ignore the triploid nature of endosperm. In this article, a statistical method considering the triploid nature of endosperm (triploid method) is developed on the basis of multiple-interval mapping (MIM) to map for the underlying QTL. The proposed triploid MIM method is derived to broadly use the marker information either from only the maternal plants or from both the maternal plants and their embryos in the backcross and F2 populations for mapping endosperm traits. Due to the use of multiple intervals simultaneously to take multiple QTL into account, the triploid MIM method can provide better detection power and estimation precision, and as shown in this article it is capable of analyzing and searching for epistatic QTL directly as compared to the traditional diploid methods and current triploid methods using only one (or two) interval(s). Several important issues in endosperm trait mapping, such as the relation and differences between the diploid and triploid methods, variance components of genetic variation, and the problems if effects are present and ignored, are also addressed. Simulations are performed to further explore these issues, to investigate the relative efficiency of different experimental designs, and to evaluate the performance of the proposed and current methods in mapping endosperm traits. The MIM-based triploid method can provide a powerful tool to estimate the genetic architecture of endosperm traits and to assist the marker-assisted selection for the improvement of grain quality in crop science. The triploid MIM FORTRAN program for mapping endosperm traits is available on the worldwide web (http://www.stat.sinica.edu.tw/chkao/).     

A Deterministic Method for Deriving Site-Specific Human Health Assessment Criteria for Contaminants in Soil

A method for deriving Site-Specific Assessment Criteria (SSAC) for use when considering risk to human health from chronic exposure to heavy metals (except lead), metalloids, and organic substances in soil, with application to the United Kingdom (UK), is described. The SSAC represents the soil concentration above which an unacceptable risk to human health may be indicated.

The method considers the UK standard land uses (residential with and without plant uptake, allotment gardens, and commercial/industrial) by applying the default exposure factors and algorithms provided. Non-standard land uses can be also considered. Site-specific determinations of contaminant bioaccessibility or of plant-to-soil concentration factors may be used if available.

The method adopts the risk-based source-pathway-receptor pollutant linkage framework and a deterministic methodology. Exposure pathways considered are direct ingestion of soil and dust, consumption of home grown or allotment vegetables, ingestion of soil attached to such vegetables, inhalation of soil vapors outdoors and inhalation of soil vapors indoors. A test for the significance of the dermal pathway is also included.

It is not intended that the method be used to generate or replace UK Soil Guideline Values, because this can only be done by the appropriate authoritative bodies within the UK (Department of the Environment, Food and Rural Affairs and the Environment Agency).     

Mapping of QTL for Body Conformation and Behavior in Cattle

Genome scans for quantitative trait loci (QTL) in farm animals have concentrated on primary production and health traits, and information on QTL for other important traits is rare. We performed a whole genome scan in a granddaughter design to detect QTL affecting body conformation and behavior in dairy cattle. The analysis included 16 paternal half-sib families of the Holstein breed with 872 sons and 264 genetic markers. The markers were distributed across all 29 autosomes and the pseudoautosomal region of the sex chromosomes with average intervals of 13.9 cM and covering an estimated 3155.5 cM. All families were analyzed jointly for 22 traits using multimarker regression and significance thresholds determined empirically by permutation. QTL that exceeded the experiment-wise significance threshold (5% level) were detected on chromosome 6 for foot angle, teat placement, and udder depth, and on chromosome 29 for temperament. QTL approaching experiment-wise significance (10% level) were located on chromosome 6 for general quality of feet and legs and general quality of udder, on chromosome 13 for teat length, on chromosome 23 for general quality of feet and legs, and on chromosome 29 for milking speed. An additional 51 QTL significant at the 5% chromosome-wise level were distributed over 21 chromosomes. This study provides the first evidence for QTL involved in behavior of dairy cattle and identifies QTL for udder conformation on chromosome 6 that could form the basis of recently reported QTL for clinical mastitis.     

Multiple interval mapping for quantitative trait loci.

A new statistical method for mapping quantitative trait loci (QTL), called multiple interval mapping (MIM), is presented. It uses multiple marker intervals simultaneously to fit multiple putative QTL directly in the model for mapping QTL. The MIM model is based on Cockerham's model for interpreting genetic parameters and the method of maximum likelihood for estimating genetic parameters. With the MIM approach, the precision and power of QTL mapping could be improved. Also, epistasis between QTL, genotypic values of individuals, and heritabilities of quantitative traits can be readily estimated and analyzed. Using the MIM model, a stepwise selection procedure with likelihood ratio test statistic as a criterion is proposed to identify QTL. This MIM method was applied to a mapping data set of radiata pine on three traits: brown cone number, tree diameter, and branch quality scores. Based on the MIM result, seven, six, and five QTL were detected for the three traits, respectively. The detected QTL individually contributed from approximately 1 to 27% of the total genetic variation. Significant epistasis between four pairs of QTL in two traits was detected, and the four pairs of QTL contributed approximately 10.38 and 14.14% of the total genetic variation. The asymptotic variances of QTL positions and effects were also provided to construct the confidence intervals. The estimated heritabilities were 0.5606, 0.5226, and 0. 3630 for the three traits, respectively. With the estimated QTL effects and positions, the best strategy of marker-assisted selection for trait improvement for a specific purpose and requirement can be explored. The MIM FORTRAN program is available on the worldwide web (http://www.stat.sinica.edu.tw/chkao/).     

FunMap: functional mapping of complex traits

SUMMARY: FunMap is a Web-based user interface designed to map quantitative trait loci (QTL) affecting function-valued traits or infinite-dimensional traits in well-structured pedigrees or natural populations. User input includes three files: longitudinal trait data, marker genotypes and/or a linkage map. This software allows for a systematic genome-wide scan and significance test of QTL throughout the map. The dynamic change of QTL effects during the time course of growth is automatically drawn, from which specific biological hypotheses regarding the genetic control mechanisms of growth and development can be tested. AVAILABILITY: http://web.biostat.ufl.edu/~cma/genetics/software.html     

Morphological and sexual traits in Atlas and Iberian Pied Flycatchers Ficedula hypoleuca speculigera and F. h. iberiae: a comparison

Capsule: There are significant biometric differences between Pied Flycatchers from Iberian and north African populations which are consistent with proposals to classify the two forms into separate species.

Aims: To determine the similarities and differences in the main biometrical and plumage sex traits between populations of the Iberian Pied Flycatcher Ficedula hypoleuca iberiae and the Atlas Flycatcher Ficedula hypoleuca speculigera.

Methods: Biometric and plumage traits of 193 breeding individuals of Iberian Pied Flycatchers and 43 Atlas Flycatchers were measured in 2014 with standardized protocols.

Results: Both sexes of Atlas Flycatchers were larger than Iberian Pied Flycatchers in skeletal (tarsus) and wing size and also differed in bill morphology, which was wider but shallower in speculigera than iberiae, with females (but not males) having shorter bills than iberiae females. Males differed in mantle colour and forehead patch size, with speculigera males being darker and displaying larger forehead patches than iberiae males. As in populations of iberiae, some speculigera females also expressed a white forehead patch.

Conclusion: We demonstrate significant phenotypic differences between Iberian Pied Flycatchers and Atlas Flycatchers with respect to size and traits of ecological and evolutionary relevance, supporting the recently proposed scenarios on their independent evolution.     

Proteomics for early detection of colorectal cancer: recent updates

Introduction: Colorectal cancer (CRC) is a common type of cancer with a relatively poor survival rate. The survival rate of patients could be improved if CRC is detected early. Biomarkers associated with early stages of tumor development might provide useful tools for the early diagnosis of colorectal cancer.

Areas covered: Online searches using PubMed and Google Scholar were performed using keywords and with a focus on recent proteomic studies. The aim of this review is to highlight the need for biomarkers to improve the detection rate of early CRC and provide an overview of proteomic technologies used for biomarker discovery and validation. This review will also discuss recent proteomic studies which focus on identifying biomarkers associated with the early stages of CRC development.

Expert commentary: A large number of CRC biomarkers are increasingly being identified by proteomics using diverse approaches. However, the clinical relevance and introduction of these markers into clinical practice cannot be determined without a robust validation process. The size of validation cohorts remains a major limitation in many biomarker studies.     

Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis

Context: Metabolic imbalance in renal cell carcinoma (RCC) can lead to abnormal adiponectin levels.

Objective: To evaluate circulating adiponectin as a detection or predictive marker for RCC.

Methods: A comprehensive literature search and meta-analysis was performed on studies reporting circulating adiponectin levels and RCC. The meta-analysis was performed using RevMan.

Results: Seven studies compared the circulating adiponection levels between RCC cases and controls. Adiponectin level was significantly lower in RCC cases compared to controls at pre-diagnosis and pre-operative time-points. RCC stage, grade and subtype did not affect adiponectin levels.

Conclusion: Low circulating adiponectin could be a predictive or risk factor for RCC.     

Sexual dimorphism and sex determination in Black-necked Grebes Podiceps nigricollis: on the need to account for geographical variation in morphology and sex ratio

Capsule: The sex of Black-necked Grebes Podiceps nigricollis in Spain can be determined successfully using a locally derived discriminant function analysis (DFA) but a function derived from a North American population was not successful.

Aims: To determine the extent of sexual size dimorphism in the Black-necked Grebe and develop discriminant functions based on morphometric data. We also assessed the accuracy of visual sexing by fieldworkers with different levels of experience and compared the discriminant function for European birds with one for North American birds, in order to determine the geographical specificity of the function.

Methods: We used a data set of 370 Black-necked Grebes from a European population throughout the non-breeding seasons of 2008–11 in the Odiel saltmarshes (Spain), as well as published data from North America, to compare the accuracy of DFAs developed for European and North American populations when applied to the same population.

Results: Males were significantly larger than females for all body measurements. The DFA with the highest success rate included one single linear dimension (head-bill length), showing an efficiency of 88.5% in the same sample used to build the function and up to 91.5% in independent samples of birds. The more experienced ringer showed higher accuracy in visual sexing than the less experienced one (84 vs. 70%), although self-consistency in sex assignment of a given individual was similar. The function developed for European birds performed poorly for American birds (79.1% sexed correctly) and vice versa (18.4% sexed correctly).

Conclusion: Morphological and sex ratio differences between European and American subspecies both contribute to the discrepancy in the success rate. This illustrates the need for caution when applying discriminant functions developed in one bird population to individuals elsewhere.     

An efficient Bayesian model selection approach for interacting quantitative trait loci models with many effects

We extend our Bayesian model selection framework for mapping epistatic QTL in experimental crosses to include environmental effects and gene-environment interactions. We propose a new, fast Markov chain Monte Carlo algorithm to explore the posterior distribution of unknowns. In addition, we take advantage of any prior knowledge about genetic architecture to increase posterior probability on more probable models. These enhancements have significant computational advantages in models with many effects. We illustrate the proposed method by detecting new epistatic and gene-sex interactions for obesity-related traits in two real data sets of mice. Our method has been implemented in the freely available package R/qtlbim (http://www.qtlbim.org) to facilitate the general usage of the Bayesian methodology for genomewide interacting QTL analysis.     

Identification of acute myocardial infarction in elderly patients using optimized highly sensitive troponin I thresholds

Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs.

Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission.

Results: Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis (p?<?0.001). According to the AUROC, hs-cTnI was a strong marker for detection of AMI in elderly patients. Application of the 99th percentile cutoffs showed a substantially lower specificity in elderly. By using optimized thresholds, specificity was improved to levels as in younger patients in both cohorts but accompanied with a decrease in sensitivity.

Conclusions: hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.     

Brood sex ratio in expansive and non-expansive tern species in east-central Poland

Capsule Evidence from two tern species does not support the theory that species in expansion should bias their brood sex ratios towards the more dispersing sex.

Aims Sex ratio theory predicts that when a species is in expansion, the sex ratio should be biased towards the more dispersing sex. We compared the sex ratio of nestlings in two closely related species of terns, characterized by different expansion rates: the White-winged Tern Chlidonias leucopterus (an expansive species) and the Black Tern Chlidonias niger (a non-expansive species).

Methods The fieldwork was carried out in the valleys of the Rivers Bug and Narew in east-central Poland, from 2008 to 2014, during which time eight White-winged Tern colonies and ten Black Tern colonies were monitored. Nest inspections began around 15–20 May, when the first eggs were laid, and continued until mid-July, when the last nestlings were 7–20 days old.

Results The nestling sex ratios were similar in both species, and the differences between number of females and males were not significant (White-winged Tern: 56.6% females vs. 43.4% males; Black Tern: 57.4% females vs. 42.6% males).

Conclusions The lack of differences in nestling sex ratio in these species may be due to the cessation of the White-winged Tern's expansion in this area or because the sex ratio is characteristic of Sternidae species, as similar results have been reported for other tern species.     

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial

Background: Medication adherence is critical for success of clinical trials.

Objective: To assess oral riboflavin is an adherence marker.

Methods: Riboflavin was incorporated into active treatment and placebo pills for a clinical trial lasting for 2 years.

Results: The accuracy (area under the receiver operating curve) of urinary riboflavin was 0.91 as a binary classifier of adherence, and was similar or better than for two active study ingredients daidzein (0.92) and genistein (0.87) (all p?<?0.0001). Decreased adherence over time was similar in the two study groups.

Conclusion: Riboflavin is an accurate and useful biomarker for study pill ingestion.     

Sex hormone-binding globulin and thrombin generation in women using hormonal contraception

Objectives: We investigated the impact of serum sex hormone-binding globulin (SHBG) on thrombin generation (TG) in women according to hormonal contraception.

Patients and methods: A cross-sectional study of SHBG and TG measured via calibrated automated thrombography was conducted in 150 healthy women, including 75 users of combined oral contraceptives (COC), 22 users of progestin-only contraceptives (POC) and 53 nonusers.

Results: COC but not POC-users had significantly higher SHBG levels compared with nonusers. In hormonal contraceptive users, SHBG was positively associated with both activated protein C (APC) resistance and baseline TG, and protein S and prothrombin were important mediators.

Conclusion: These data provide further evidence that SHBG may be used as a biomarker in assessing prothrombotic profile of hormonal contraception.     

QTL affecting conformation traits in Angora goats

A genomic screen for quantitative trait loci (QTL) affecting conformation traits was performed by genotyping 288 Angora goats offspring from 8 half-sub families with 76 microsatellite markers. The following traits were recorded: weaning weight (WW, Kg); stature (S, cm); chest depth (CD, cm); shoulder width (SW, cm); rump length (RL, cm); rump width (RW, cm); head length (HL, cm); head width (HW, cm); shin circumference (SC, cm); chest circumference (CC, cm) and body length (BL, cm). Data were analyzed using the QTL Express program. A total of 5 QTL were detected in five chromosomes with chromosome wide significance level. For the 11 analysed traits the results were: evidence of two possible QTL for HL were found in chromosomes 1 and 4, a putative QTL for trait CD was found in chromosome 2, evidence for BL was found in chromosome 8 and a possible QTL was found for trait CC in chromosome 9. The results reported here show the existence of chromosomal regions in Angora goats involved in conformation traits and represent the first in depth search in some specific-genome sections in order to identify and characterize the genetic variability involved in these traits.