Em 1999, Pereira e Stern [Pereira and Stern, 1999] propuseram o Full Baye- sian Significance Test (FBST), ou Teste de Significancia Completamente Bayesiano, especialmente desenhado para fornecer um valor de evidencia dando suporte a uma hip otese precisa H. Apesar de possuir boas propriedades conceituais e poder tratar virtual- mente quaisquer classes de hip oteses precisas em modelos param etricos, a difus ao deste m etodo na comunidade cient fica tem sido fortemente limitada pela ausencia de um ambiente integrado onde o pesquisador possa formular e implementar o teste de seu interesse. O objetivo deste trabalho e apresentar uma proposta de implementa c ao de um ambiente integrado para o FBST, que seja suficientemente flex vel para tratar uma grande classe de problemas. Como estudo de caso, apresentamos a formula c ao do FBST para um problema cl assico em gen etica populacional, o Equil brio de Hardy-Weinberg / In 1999, Pereira and Stern [Pereira and Stern, 1999] introduced the Full Bayesian Significance Test (FBST), developed to give a value of evidence for a precise hypothesis H. Despite having good conceptual properties and being able to dealing with virtually any classes of precise hypotheses under parametric models, the FBST did not achieve a large difusion among the academic community due to the abscence of an computational environment where the researcher can define and assess the evidence for hypothesis under investigation. In this work we propose an implementation of an flexible computatio- nal environment for FBST and show a case study in a classical problem in population genetics, the Hardy-Weinberg Equilibrium Law.

Em 1999, Pereira e Stern [Pereira and Stern, 1999] propuseram o Full Baye- sian Significance Test (FBST), ou Teste de Significancia Completamente Bayesiano, especialmente desenhado para fornecer um valor de evidencia dando suporte a uma hip otese precisa H. Apesar de possuir boas propriedades conceituais e poder tratar virtual- mente quaisquer classes de hip oteses precisas em modelos param etricos, a difus ao deste m etodo na comunidade cient fica tem sido fortemente limitada pela ausencia de um ambiente integrado onde o pesquisador possa formular e implementar o teste de seu interesse. O objetivo deste trabalho e apresentar uma proposta de implementa c ao de um ambiente integrado para o FBST, que seja suficientemente flex vel para tratar uma grande classe de problemas. Como estudo de caso, apresentamos a formula c ao do FBST para um problema cl assico em gen etica populacional, o Equil brio de Hardy-Weinberg / In 1999, Pereira and Stern [Pereira and Stern, 1999] introduced the Full Bayesian Significance Test (FBST), developed to give a value of evidence for a precise hypothesis H. Despite having good conceptual properties and being able to dealing with virtually any classes of precise hypotheses under parametric models, the FBST did not achieve a large difusion among the academic community due to the abscence of an computational environment where the researcher can define and assess the evidence for hypothesis under investigation. In this work we propose an implementation of an flexible computatio- nal environment for FBST and show a case study in a classical problem in population genetics, the Hardy-Weinberg Equilibrium Law.

In an unpublished study in Toronto it was observed that cases were in Hardy-Weinberg Equilibrium at a locus whereas their family members were in Hardy-Weinberg Disequilibrium (HWD). This led to an investigation of relatives of affected individuals to see whether the multiplicative model could be revealed by a nonzero HWD coefficient in relatives. Genotypic frequencies and HWD coefficients were derived for affected individuals and their affected and unaffected relatives. Methods were also developed to test for association using data from affected individuals and their relatives. In addition, a model was developed to assess whether the HWD observed in a data set from a stratified population can be explained by both genetic association and stratification. Parameter estimates for these models can be obtained using maximum likelihood methods, and used to deduce the mode of inheritance of the disease. / Departure from HWE (HWD) in a sample may indicate genotyping error, population stratification, selection bias, or some combination thereof. Therefore, loci exhibiting HWD are often excluded from association studies. However, it has been shown that in case-control studies HWD can result from a genetic effect at the locus, and HWD at a marker locus can be interpreted as evidence for association with a disease. In an unpublished study in Toronto it was observed that cases were in Hardy- Weinberg equilibrium at a locus whereas their family members were in HWD. It has been shown that the HWD coefficient for a multiplicative genetic model is zero. This led to an investigation of relatives of affected individuals to see whether the multiplicative model could be revealed by a nonzero HWD coefficient in relatives. Genotypic frequencies and HWD coefficients were derived for affected individuals and their affected and unaffected relatives. A substantial HWD was found in both individuals in dominant and recessive genetic models but HWD is only slightly nonzero for additive and multiplicative models. Methods were also developed to test for association using data from affected individuals and their relatives. Parameter estimates for these models can be obtained using maximum likelihood methods, and estimates provide valuable information regarding the mode of inheritance of the disease. The methods were applied to 112 discordant sib pairs with Alzheimer’s disease typed for the ApoE polymorphism and a significant association was observed between the "4 ApoE allele and Alzheimer’s disease. Case-control studies may indicate spurious association with a marker locus in a stratified population. Methods were developed to determine if the HWD observed in a data set from a stratified population can be explained by both genetic association and stratification. Parameter estimates for these models can be obtained using maximum likelihood methods, and used to deduce the mode of inheritance of the disease. Applying the model to the R990G SNP of the CASR gene, it was found that the HWD was adequately explained by a recessive genetic association and a stratification proportion of 10%, consistent with the population of Toronto.

Natural selection and other components of evolutionary theory are known to be particularly challenging concepts for students to understand. To help illustrate these concepts, we developed a simulation model of microevolutionary processes. The model features all the components of Hardy-Weinberg theory, with population size, selection, gene flow, nonrandom mating, and mutation all being demonstrated in the simulations. By using this freely available computer model, students can develop and test hypotheses with replicated virtual experiments. Because the model is an agent-based simulation, there is biologically realistic variability in the results. Students using the model see results both numerically and graphically and these are reinforced by an animation of the virtual fish in the simulated experiment.

Alleles, genotypes and haplotypes (combinations of alleles) have been widely used in gene-disease association studies. More recently, association studies using diplotypes (haplotype pairs on homologous chromosomes) have become increasingly common. This article reviews the rationale of the four types of association analyses and discusses the situations in which diplotype-based analyses are more powerful than the other types of association analyses. Haplotype-based association analyses are more powerful than allele-based association analyses, and diplotype-based association analyses are more powerful than genotype-based analyses. In circumstances where there are no interaction effects between markers and where the criteria for Hardy-Weinberg Equilibrium (HWE) are met, the larger sample size and smaller degrees of freedom of allele-based and haplotype-based association analyses make them more powerful than genotype-based and diplotype-based association analyses, respectively. However, under certain circumstances diplotype-based analyses are more powerful than haplotype-based analysis.

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<p>The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc.</p><p>The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE.</p><p>Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population.</p><p>It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.</p>

The breakdown of self-tolerance is the main driving force behind susceptibility to SLE. When this occurs, T and B cells are activated in an uncontrolled manner and produce autoantibodies against self fragmented DNA, RNA and sometimes other parts of the cell such as cardiolipin, phosphatidylserine, etc. The mechanism behind the breakdown of self-tolerance may be genetic factors that are triggered by environmental factors. SLE is not caused by a single gene, but by many genes, and is thus a polygenic disease. So far only a few genes have been found to be associated with SLE including PDCD1, FcγRs, and PTPN22. The main aim of my thesis is to find susceptibility genes responsible for SLE. Recently, a gene called IRF5 was found to be associated with SLE. In paper one, we performed a thorough study and confirmed its association to SLE. In addition, we found a few other SNPs in the gene that were associated to the disease. Among them, SNP rs2004640 is very strongly associated and was found to affect the splicing of the gene. Another SNP, rs2280714, correlated with overexpression of the gene, although SNP rs10954213 was much more highly correlated with expression adding to this, in paper two we found a few other SNPs that were associated to SLE and played crucial roles in gene function. An indel in exon 6, though not associated by itself, regulated which isoforms were expressed. Individuals with 2 repeats expressed isoforms V1 and V4, while individuals with 4 repeats expressed isoforms V5 and V6. SNP rs2070197 was also very strongly associated, but did not have a functional role. In paper three, the same polymorphisms were studied in a Mexican population, which showed an even stronger association when compared to a European population. It is known that autoimmune diseases share susceptibility genes, therefore we wanted to see if the IRF5 gene is associated with any other autoimmune diseases. In papers four and five, we tested its association to RA (using three sets of patients and controls from Sweden, Argentina and Spain) and psoriasis (using a set of patients and controls from Sweden). Association was not found in either of the diseases. Therefore, we believe that this association may be SLE-specific.