Simulation and graph mining tools for improving gene mapping efficiency

Gene mapping is a systematic search for genes that affect observable characteristics of an organism. In this thesis we offer computational tools to improve the efficiency of (disease) gene-mapping efforts. In the first part of the thesis we propose an efficient simulation procedure for generating realistic genetical data from isolated populations. Simulated data is useful for evaluating hypothesised gene-mapping study designs and computational analysis tools. As an example of such evaluation, we demonstrate how a population-based study design can be a powerful alternative to traditional family-based designs in association-based gene-mapping projects. In the second part of the thesis we consider a prioritisation of a (typically large) set of putative disease-associated genes acquired from an initial gene-mapping analysis. Prioritisation is necessary to be able to focus on the most promising candidates. We show how to harness the current biomedical knowledge for the prioritisation task by integrating various publicly available biological databases into a weighted biological graph. We then demonstrate how to find and evaluate connections between entities, such as genes and diseases, from this unified schema by graph mining techniques. Finally, in the last part of the thesis, we define the concept of reliable subgraph and the corresponding subgraph extraction problem. Reliable subgraphs concisely describe strong and independent connections between two given vertices in a random graph, and hence they are especially useful for visualising such connections. We propose novel algorithms for extracting reliable subgraphs from large random graphs. The efficiency and scalability of the proposed graph mining methods are backed by extensive experiments on real data. While our application focus is in genetics, the concepts and algorithms can be applied to other domains as well. We demonstrate this generality by considering coauthor graphs in addition to biological graphs in the experiments.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation=161024). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve cells, P,0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells.

Thrombotic Antiphospholipid Syndrome Shows Strong Haplotypic Association with SH2B3-ATXN2 Locus

Background : Thrombotic antiphospholipid syndrome is defined as a complex form of thrombophilia that is developed by a fraction of antiphospholipid antibody (aPLA) carriers. Little is known about the genetic risk factors involved in thrombosis development among aPLA carriers. Methods: To identify new loci conferring susceptibility to thrombotic antiphospholipid syndrome, a two-stage genotyping strategy was performed. In stage one, 19,000 CNV loci were genotyped in 14 thrombotic aPLA+ patients and 14 healthy controls by array-CGH. In stage two, significant CNV loci were fine-mapped in a larger cohort (85 thrombotic aPLA+, 100 non-thrombotic aPLA+ and 569 healthy controls). Results : Array-CGH and fine-mapping analysis led to the identification of 12q24.12 locus as a new susceptibility locus for thrombotic APS. Within this region, a TAC risk haplotype comprising one SNP in SH2B3 gene (rs3184504) and two SNPs in ATXN2 gene (rs10774625 and rs653178) exhibited the strongest association with thrombotic antiphospholipid syndrome (p-value = 5,9 × 10−4 OR 95% CI 1.84 (1.32–2.55)). Conclusion : The presence of a TAC risk haplotype in ATXN2-SH2B3 locus may contribute to increased thrombotic risk in aPLA carriers.

Structure learning in a sensorimotor association task.

Learning is often understood as an organism's gradual acquisition of the association between a given sensory stimulus and the correct motor response. Mathematically, this corresponds to regressing a mapping between the set of observations and the set of actions. Recently, however, it has been shown both in cognitive and motor neuroscience that humans are not only able to learn particular stimulus-response mappings, but are also able to extract abstract structural invariants that facilitate generalization to novel tasks. Here we show how such structure learning can enhance facilitation in a sensorimotor association task performed by human subjects. Using regression and reinforcement learning models we show that the observed facilitation cannot be explained by these basic models of learning stimulus-response associations. We show, however, that the observed data can be explained by a hierarchical Bayesian model that performs structure learning. In line with previous results from cognitive tasks, this suggests that hierarchical Bayesian inference might provide a common framework to explain both the learning of specific stimulus-response associations and the learning of abstract structures that are shared by different task environments.

Mapping the shallow-water coral ecosystems of the Freely Associated States: an implementation plan

This Freely Associated States Shallow-water Coral Ecosystem Mapping Implementation Plan (FAS MIP) presents a framework for the development of shallow-water (~0–40 m; 0–22 fm) benthic habitat and possibly bathymetric maps of critical areas of the Freely Associated States (FAS). The FAS is made up of three self-governing groups of islands and atolls—the Republic of Palau (Palau), the Federated States of Micronesia (FSM), and the Republic of the Marshall Islands (RMI)—that are affiliated with the United States through Compacts of Free Association. This MIP was developed with extensive input from colleges, national and state regulatory and management agencies, federal agencies, non-governmental organizations, and individuals involved in or supporting the conservation and management of the FAS’s coral ecosystems. A list of organizations and individuals that provided input to the development of this MIP is provided in Appendix 1. This MIP has been developed to complement the Coral Reef Mapping Implementation Plan (2nd Draft) released in 1999 by the U.S. Coral Reef Task Force’s Mapping and Information Synthesis Working Group. That plan focused on mapping United States and FAS shallow-water (then defined as <30 m) coral reefs by 2009, based on available funding and geographic priorities, using primarily visual interpretation of aerial photography and satellite imagery. This MIP focuses on mapping the shallow-water (now defined as 0–40 m, rather than 0–30 m) coral ecosystems of the FAS using a suite of technologies and map development procedures. Both this FAS MIP and the 1999 Coral Reef Mapping Implementation Plan (2nd Draft) support to goals of the National Action Plan to Conserve Coral Reefs (U.S. Coral Reef Task Force, 2000). This FAS MIP presents a framework for mapping the coral ecosystems of the FAS and should be considered an evolving document. As priorities change, funding opportunities arise, new data are collected, and new technologies become available, the information presented herein will change.

Mapping of the Indian fisheries growth rate and fish consumption through GIS

In the present study, Indian fisheries growth rate and fish consumption have been analyzed through GIS mapping. The analyses were based on the state-level fisheries data of India collected from the secondary sources. Accordingly, the paper contains one thematic map containing two layers. To achieve this, all the data have been brought into a tabular form through Microsoft Excel and then joined to Map Info Professional Version 8.0 GIS software with digitized map of India for further analysis to generate thematic maps. In this thematic map, the first Jayer represents the growth-rate of fish production for the period 1990-2004 and the second layer represents fish consumption for the year 2003. The thematic map represented in graphic form presents inland, marine and total growth rates, and also the rural and urban fish consumption at the state levels. This study will be useful to fish traders, planners, researchers and administrators in fisheries policy formulation for sustainable development.

Fisheries profile mapping of coastal districts in Maharashtra state through GIS

In recent times, GIS is being increasingly used as a decision support system for management of fisheries and aquaculture. It provides new innovative approaches of the dynamic relations that characterize this sector. In this context, a study is conducted based on the secondary data of a major maritime state, Maharashtra, where mapping of fisheries profile of coastal districts in the state is performed through GIS tool having critical geographic dimensions. This paper aims to map information of the state which can be used for the purpose of planning and decision making as each aspect of map has a different component involved. For this purpose, at the core of the system, the data were accessed and integrated from different sources mainly from the five coastal districts of Maharashtra state. Data were brought in tabular form through Microsoft Excel and then joined to Map info Professional version 8.0 GIS software was used with the digitized map of Maharashtra state to enable mapping. This was further synchronized and integrated to generate four thematic maps searchable on several criteria. Map 1 contains the searchable criteria as regards to the fish growth for the year 1997-2004 and fish seed production for the year 2003-04. Map 2 contains fisher population along with their occupation for the year 1992. Map 3 contains brackish water and shrimp farming production and culture area. Map 4 contains infrastructural facilities which include type of boats etc. With this mapping, planners and various stakeholders have accessible information as regards to the various components of fisheries in the state of Maharashtra.

Identification and mapping of amplified fragment length polymorphism markers linked to shell color in bay scallop, Argopecten irradians irradians (Lamarck, 1819)

Amplified fragment length polymorphisms (AFLP) were used to study the inheritance of shell color in Argopecten irradians. Two scallops, one with orange and the other with white shells, were used as parents to produce four F-1 families by selfing and outcrossing. Eighty-eight progeny, 37 orange and 51 white, were randomly selected from one of the families for segregation and mapping analysis with AFLP and microsatellite markers. Twenty-five AFLP primer pairs were screened, yielding 1138 fragments, among which 148 (13.0%) were polymorphic in two parents and segregated in progeny. Six AFLP markers showed significant (P < 0.05) association with shell color. All six loci were mapped to one linkage group. One of the markers, F1f335, is completely linked to the gene for orange shell, which we designated as Orange1, without any recombination in the progeny we sampled. The marker was amplified in the orange parent and all orange progeny, but absent in the white parent and all the white progeny. The close linkage between F1f335 and Orange1 was validated using bulk segregation analysis in two natural populations, and all our data indicate that F1f335 is specific for the shell color gene, Orange1. The genomic mapping of a shell color gene in bay scallop improves our understanding of shell color inheritance and may contribute to the breeding of molluscs with desired shell colors.

Improved delineation of short cortical association fibers and gray/white matter boundary using whole-brain three-dimensional diffusion tensor imaging at submillimeter spatial resolution.

Recent emergence of human connectome imaging has led to a high demand on angular and spatial resolutions for diffusion magnetic resonance imaging (MRI). While there have been significant growths in high angular resolution diffusion imaging, the improvement in spatial resolution is still limited due to a number of technical challenges, such as the low signal-to-noise ratio and high motion artifacts. As a result, the benefit of a high spatial resolution in the whole-brain connectome imaging has not been fully evaluated in vivo. In this brief report, the impact of spatial resolution was assessed in a newly acquired whole-brain three-dimensional diffusion tensor imaging data set with an isotropic spatial resolution of 0.85 mm. It was found that the delineation of short cortical association fibers is drastically improved as well as the definition of fiber pathway endings into the gray/white matter boundary-both of which will help construct a more accurate structural map of the human brain connectome.

Application of a rank-based genetic association test to age-at-onset data from the Collaborative Study on the Genetics of Alcoholism study.

Association studies of quantitative traits have often relied on methods in which a normal distribution of the trait is assumed. However, quantitative phenotypes from complex human diseases are often censored, highly skewed, or contaminated with outlying values. We recently developed a rank-based association method that takes into account censoring and makes no distributional assumptions about the trait. In this study, we applied our new method to age-at-onset data on ALDX1 and ALDX2. Both traits are highly skewed (skewness > 1.9) and often censored. We performed a whole genome association study of age at onset of the ALDX1 trait using Illumina single-nucleotide polymorphisms. Only slightly more than 5% of markers were significant. However, we identified two regions on chromosomes 14 and 15, which each have at least four significant markers clustering together. These two regions may harbor genes that regulate age at onset of ALDX1 and ALDX2. Future fine mapping of these two regions with densely spaced markers is warranted.

Recovery of a biodiversity action plans species in northwest England: possible role of climate change, artificial habitat and water quality amelioration. Occasional Publication of the Marine Biological Association 16

The honeycomb reef worm Sabellaria alveolata is recognised as being an important component of intertidal communities. It is a priority habitat within the UK Biodiversity Action Plan and as a biogenic reef forming species is covered by Annex 1 of the EC habitats directive. S. alveolata has a lusitanean (southern) distribution, being largely restricted to the south and west coasts of England. A broad-scale survey of S. alveolata distribution along the north-west coasts was undertaken in 2003/2004. These records were then compared with previous distribution records, mainly those collected by Cunningham in 1984. More detailed mapping was carried out at Hilbre Island at the mouth of the River Dee, due to recent reports that S. alveolata had become re-established there after a long absence.