Bayesian refinement of protein functional site matching

<p>Abstract</p> <p>Background</p> <p>Matching functional sites is a key problem for the understanding of protein function and evolution. The commonly used graph theoretic approach, and other related approaches, require adjustment of a matching distance threshold <it>a priori </it>according to the noise in atomic positions. This is difficult to pre-determine when matching sites related by varying evolutionary distances and crystallographic precision. Furthermore, sometimes the graph method is unable to identify alternative but important solutions in the neighbourhood of the distance based solution because of strict distance constraints. We consider the Bayesian approach to improve graph based solutions. In principle this approach applies to other methods with strict distance matching constraints. The Bayesian method can flexibly incorporate all types of prior information on specific binding sites (e.g. amino acid types) in contrast to combinatorial formulations.</p> <p>Results</p> <p>We present a new meta-algorithm for matching protein functional sites (active sites and ligand binding sites) based on an initial graph matching followed by refinement using a Markov chain Monte Carlo (MCMC) procedure. This procedure is an innovative extension to our recent work. The method accounts for the 3-dimensional structure of the site as well as the physico-chemical properties of the constituent amino acids. The MCMC procedure can lead to a significant increase in the number of significant matches compared to the graph method as measured independently by rigorously derived p-values.</p> <p>Conclusion</p> <p>MCMC refinement step is able to significantly improve graph based matches. We apply the method to matching NAD(P)(H) binding sites within single Rossmann fold families, between different families in the same superfamily, and in different folds. Within families sites are often well conserved, but there are examples where significant shape based matches do not retain similar amino acid chemistry, indicating that even within families the same ligand may be bound using substantially different physico-chemistry. We also show that the procedure finds significant matches between binding sites for the same co-factor in different families and different folds.</p

Corresponding amino acids between the NAD-binding site of alcohol dehydrogenase (1hdx 1) and NADP-binding site of hypothetical protein YhdH (1o8c 1) before and after MCMC refinement step with the glycine rich motif highlighted (see main text)

<p><b>Copyright information:</b></p><p>Taken from "Bayesian refinement of protein functional site matching"</p><p>http://www.biomedcentral.com/1471-2105/8/257</p><p>BMC Bioinformatics 2007;8():257-257.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1940029.</p><p></p

Alcohol dehydrogenase NAD-binding site (1hdx 1) matching against SCOP alcohol dehydrogenase-like family

<p><b>Copyright information:</b></p><p>Taken from "Bayesian refinement of protein functional site matching"</p><p>http://www.biomedcentral.com/1471-2105/8/257</p><p>BMC Bioinformatics 2007;8():257-257.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1940029.</p><p></p> a) Graph matching prior to MCMC refinement step showing results with/without amino acid property information. Each site in the family is represented by a circle (with) and cross (without) connected by a straight line to highlight the difference. b) MCMC refinement step of (a)

Histograms and traces of parameters when matching 17 – hydroxysteroid dehydrogenase and carbonyl reductase (1cyd 1)

<p><b>Copyright information:</b></p><p>Taken from "Bayesian refinement of protein functional site matching"</p><p>http://www.biomedcentral.com/1471-2105/8/257</p><p>BMC Bioinformatics 2007;8():257-257.</p><p>Published online 17 Jul 2007</p><p>PMCID:PMC1940029.</p><p></p

Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data

Background: The -α3.7I-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies

Imputation-based meta-analysis of severe malaria in three African populations.

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles

Asiakastyytyväisyystutkimus : Simon Auto Oy

Opinnäytetyön tarkoituksena oli selvittää Pihtiputaan Simon Auto Oy:n asiakkaiden tyytyväisyyttä. Asiakkaiden tyytyväisyyttä selvitettiin myymälään ja kahvioon, sijaintiin sekä asiakaspalveluun. Tutkimuksessa selvitettiin samalla myös asiakkaiden taustatietoja sekä asiointitiheyttä. Opinnäytetyön teoriaosuudessa käsitellään palvelun laatua, markkinointia yleisellä tasolla, asiakastyytyväisyyttä sekä erilaisia tutkimustyyppejä. Lähteinä opinnäytetyössä käytettiin palvelua, markkinointia, asiakastyytyväisyyttä sekä tilastollista tutkimusta käsittelevää kirjallisuutta. Asiakastyytyväisyystutkimus suoritettiin kyselylomakkeella Pihtiputaan Simon Auto Oy:ssä. Vastauksia saatiin yhteensä 29 kappaletta. Tutkimuksen tulosten perusteella asiakaspalvelun laatuun sekä myymälään ja kahvioon oltiin pääosin tyytyväisiä.The purpose of this thesis was to study the satisfaction of the customers of Simon Auto Oy. The aim was to find out customers’ satisfaction with the store, cafeteria, location and customer service. This study also examined customers’ backgrounds and density of transactions. The theoretical part of this thesis deals with the quality of service, marketing at a general level, customer satisfaction and different research types. The sources of this thesis represented literature that covered service, marketing, customer satisfaction and statistical research. The customer satisfaction research was carried out by using questionnaire which took place at the store. The total number of answers was 29. Based on the research results, the customers were mainly contented with the quality of the customer service and with the store and the cafeteria

Verbal autopsy as a tool for identifying children dying of sickle cell disease : a validation study conducted in Kilifi district, Kenya

Background: Sickle cell disease (SCD) is common in many parts of sub-Saharan Africa (SSA), where it is associated with high early mortality. In the absence of newborn screening, most deaths among children with SCD go unrecognized and unrecorded. As a result, SCD does not receive the attention it deserves as a leading cause of death among children in SSA. In the current study, we explored the potential utility of verbal autopsy (VA) as a tool for attributing underlying cause of death (COD) in children to SCD. Methods: We used the 2007 WHO Sample Vital Registration with Verbal Autopsy (SAWY) VA tool to determine COD among child residents of the Kilifi Health and Demographic Surveillance System (KHDSS), Kenya, who died between January 2008 and April 2011. VAs were coded both by physician review (physician coded verbal autopsy, PCVA) using COD categories based on the WHO International Classification of Diseases 10(th) Edition (ICD-10) and by using the InterVA-4 probabilistic model after extracting data according to the 2012 WHO VA standard. Both of these methods were validated against one of two gold standards: hospital ICD-10 physician-assigned COD for children who died in Kilifi District Hospital (KDH) and, where available, laboratory confirmed SCD status for those who died in the community. Results: Overall, 6% and 5% of deaths were attributed to SCD on the basis of PCVA and the InterVA-4 model, respectively. Of the total deaths, 22% occurred in hospital, where the agreement coefficient (AC(1)) for SCD between PCVA and hospital physician diagnosis was 95.5%, and agreement between InterVA-4 and hospital physician diagnosis was 96.9%. Confirmatory laboratory evidence of SCD status was available for 15% of deaths, in which the AC(1) against PCVA was 87.5%. Conclusions: Other recent studies and provisional data from this study, outlining the importance of SCD as a cause of death in children in many parts of the developing world, contributed to the inclusion of specific SCD questions in the 2012 version of the WHO VA instruments, and a specific code for SCD has now been included in the WHO and InterVA-4 COD listings. With these modifications, VA may provide a useful approach to quantifying the contribution of SCD to childhood mortality in rural African communities. Further studies will be needed to evaluate the generalizability of our findings beyond our local context

A novel locus of resistance to severe malaria in a region of ancient balancing selection

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio= 0.67, 95% confidence interval= 0.60-0.76, P value= 9.5Ã\u97 10-11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection

Author response: Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

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