Fine mapping and replication of QTL in outbred chicken advanced intercross lines

Background: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. Methods: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. Results: Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. Conclusions: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed.

qtl.outbred: Interfacing outbred line cross data with the R/qtl mapping software

Background qtl.outbred is an extendible interface in the statistical environment, R, for combining quantitative trait loci (QTL) mapping tools. It is built as an umbrella package that enables outbred genotype probabilities to be calculated and/or imported into the software package R/qtl. Findings Using qtl.outbred, the genotype probabilities from outbred line cross data can be calculated by interfacing with a new and efficient algorithm developed for analyzing arbitrarily large datasets (included in the package) or imported from other sources such as the web-based tool, GridQTL. Conclusion qtl.outbred will improve the speed for calculating probabilities and the ability to analyse large future datasets. This package enables the user to analyse outbred line cross data accurately, but with similar effort than inbred line cross data.

Novel Statistical Methods in Quantitative Genetics : Modeling Genetic Variance for Quantitative Trait Loci Mapping and Genomic Evaluation

This thesis develops and evaluates statistical methods for different types of genetic analyses, including quantitative trait loci (QTL) analysis, genome-wide association study (GWAS), and genomic evaluation. The main contribution of the thesis is to provide novel insights in modeling genetic variance, especially via random effects models. In variance component QTL analysis, a full likelihood model accounting for uncertainty in the identity-by-descent (IBD) matrix was developed. It was found to be able to correctly adjust the bias in genetic variance component estimation and gain power in QTL mapping in terms of precision.  Double hierarchical generalized linear models, and a non-iterative simplified version, were implemented and applied to fit data of an entire genome. These whole genome models were shown to have good performance in both QTL mapping and genomic prediction. A re-analysis of a publicly available GWAS data set identified significant loci in Arabidopsis that control phenotypic variance instead of mean, which validated the idea of variance-controlling genes.  The works in the thesis are accompanied by R packages available online, including a general statistical tool for fitting random effects models (hglm), an efficient generalized ridge regression for high-dimensional data (bigRR), a double-layer mixed model for genomic data analysis (iQTL), a stochastic IBD matrix calculator (MCIBD), a computational interface for QTL mapping (qtl.outbred), and a GWAS analysis tool for mapping variance-controlling loci (vGWAS).

MAPfastR : quantitative trait loci mapping in outbred line crosses

MAPfastR is a software package developed to analyze QTL data from inbred and outbred line-crosses. The package includes a number of modules for fast and accurate QTL analyses. It has been developed in the R language for fast and comprehensive analyses of large datasets. MAPfastR is freely available at: http://www.computationalgenetics.se/?page_id=7.

Pedagogical methods in web-based language teaching-mapping

The purpose of this presentation is to introduce the research project progress in “the mapping of pedagogical methods in web-based language teaching" by Högskolan Dalarna (Dalarna University). This project will identify the differences in pedagogical methods that are used for online language classes. The pedagogical method defined in this project is what the teachers do to ensure students attain the learning outcomes, for example, planning, designing courses, leading students, knowing students' abilities, implementing activities, etc. So far the members of this project have analyzed the course plans (in the language department at Dalarna University) and categorized the learning outcomes. A questionnaire was constructed based on the learning outcomes and then either sent out remotely to teachers or completed face to face through interviews. The answers provided to the questionnaires enabled the project to identify many differences in how language teachers interact with their students but also, the way of giving feedback, motivating and helping students, types of class activities and materials used. This presentation introduces the progress of the project and identifies the challenges at the language department at Dalarna University. Finally, the advantages and problems of online language proficiency courses will be discussed and suggestions made for future improvement.

PokerMapper: : mapping executive functions, poker playing ability and responsible gambling in online environments

Research objectives Poker and responsible gambling both entail the use of the executive functions (EF), which are higher-level cognitive abilities. The main objective of this work was to assess if online poker players of different ability show different performances in their EF and if so, which functions are the most discriminating ones. The secondary objective was to assess if the EF performance can predict the quality of gambling, according to the Gambling Related Cognition Scale (GRCS), the South Oaks Gambling Screen (SOGS) and the Problem Gambling Severity Index (PGSI). Sample and methods The study design consisted of two stages: 46 Italian active players (41m, 5f; age 32±7,1ys; education 14,8±3ys) fulfilled the PGSI in a secure IT web system and uploaded their own hand history files, which were anonymized and then evaluated by two poker experts. 36 of these players (31m, 5f; age 33±7,3ys; education 15±3ys) accepted to take part in the second stage: the administration of an extensive neuropsychological test battery by a blinded trained professional. To answer the main research question we collected all final and intermediate scores of the EF tests on each player together with the scoring on the playing ability. To answer the secondary research question, we referred to GRCS, PGSI and SOGS scores.  We determined which variables that are good predictors of the playing ability score using statistical techniques able to deal with many regressors and few observations (LASSO, best subset algorithms and CART). In this context information criteria and cross-validation errors play a key role for the selection of the relevant regressors, while significance testing and goodness-of-fit measures can lead to wrong conclusions.   Preliminary findings We found significant predictors of the poker ability score in various tests. In particular, there are good predictors 1) in some Wisconsin Card Sorting Test items that measure flexibility in choosing strategy of problem-solving, strategic planning, modulating impulsive responding, goal setting and self-monitoring, 2) in those Cognitive Estimates Test variables related to deductive reasoning, problem solving, development of an appropriate strategy and self-monitoring, 3) in the Emotional Quotient Inventory Short (EQ-i:S) Stress Management score, composed by the Stress Tolerance and Impulse Control scores, and in the Interpersonal score (Empathy, Social Responsibility, Interpersonal Relationship). As for the quality of gambling, some EQ-i:S scales scores provide the best predictors: General Mood for the PGSI; Intrapersonal (Self-Regard; Emotional Self-Awareness, Assertiveness, Independence, Self-Actualization) and Adaptability  (Reality Testing, Flexibility, Problem Solving) for the SOGS, Adaptability for the GRCS. Implications for the field Through PokerMapper we gathered knowledge and evaluated the feasibility of the construction of short tasks/card games in online poker environments for profiling users’ executive functions. These card games will be part of an IT system able to dynamically profile EF and provide players with a feedback on their expected performance and ability to gamble responsibly in that particular moment. The implementation of such system in existing gambling platforms could lead to an effective proactive tool for supporting responsible gambling. 

Genome-wide association mapping in a wild avian population identifies a link between genetic and phenotypic variation in a life-history trait

Understanding the genetic basis of traits involved in adaptation is a major challenge in evolutionary biology but remains poorly understood. Here, we use genome-wide association mapping using a custom 50 k single nucleotide polymorphism (SNP) array in a natural population of collared flycatchers to examine the genetic basis of clutch size, an important life-history trait in many animal species. We found evidence for an association on chromosome 18 where one SNP significant at the genome-wide level explained 3.9% of the phenotypic variance. We also detected two suggestive quantitative trait loci (QTLs) on chromosomes 9 and 26. Fitness differences among genotypes were generally weak and not significant, although there was some indication of a sex-by-genotype interaction for lifetime reproductive success at the suggestive QTL on chromosome 26. This implies that sexual antagonism may play a role in maintaining genetic variation at this QTL. Our findings provide candidate regions for a classic avian life-history trait that will be useful for future studies examining the molecular and cellular function of, as well as evolutionary mechanisms operating at, these loci.

Mapping Attribution Metadata to the Open Provenance Model

A description of a data item's provenance can be provided in dierent forms, and which form is best depends on the intended use of that description. Because of this, dierent communities have made quite distinct underlying assumptions in their models for electronically representing provenance. Approaches deriving from the library and archiving communities emphasise agreed vocabulary by which resources can be described and, in particular, assert their attribution (who created the resource, who modied it, where it was stored etc.) The primary purpose here is to provide intuitive metadata by which users can search for and index resources. In comparison, models for representing the results of scientific workflows have been developed with the assumption that each event or piece of intermediary data in a process' execution can and should be documented, to give a full account of the experiment undertaken. These occurrences are connected together by stating where one derived from, triggered, or otherwise caused another, and so form a causal graph. Mapping between the two approaches would be benecial in integrating systems and exploiting the strengths of each. In this paper, we specify such a mapping between Dublin Core and the Open Provenance Model. We further explain the technical issues to overcome and the rationale behind the approach, to allow the same method to apply in mapping similar schemes.

Mapping of Diepoxybutane Damage in the Cytochrome b Domain of Mitochondrial DNA and the β-globin Domain of Nuclear Chicken DNA Using Quantitative PCR

Diepoxybutane (DEB), a known industrial carcinogen, reacts with DNA primarily at the N7 position of deoxyguanosine residues and creates interstrand cross-links at the sequence 5'-GNC. Since N7-N7 cross-links cause DNA to fragment upon heating, quantative polymerase chain reaction (QPCR) is being used in this experiment to measure the amount of DEB damage (lesion frequency) with three different targets-mitochondrial (unpackaged), open chromatin region, and closed chromatin region. Initial measurements of DEB damage within these three targets were not consistent because the template DNA was not the limiting reagent in the PCR. Follow-up PCR trials using a limiting amount of DNA are still in progress although initial experimentation looks promising. Sequencing of these three targets to confirm the primer targets has only been successfully performed for the closed chromatin target and does not match the sequence from NIH used to design that primer pair. Further sequencing trials need to be conducted on all three targets to assure that a mitochondrial, open chromatin, and closed chromatin region are actually being amplified in this experimental series.