BAPS 2: enhanced possibilities for the analysis of genetic population structure

Bayesian statistical methods based on simulation techniques have recently been shown to provide powerful tools for the analysis of genetic population structure. We have previously developed a Markov chain Monte Carlo (MCMC) algorithm for characterizing genetically divergent groups based on molecular markers and geographical sampling design of the dataset. However, for large-scale datasets such algorithms may get stuck to local maxima in the parameter space. Therefore, we have modified our earlier algorithm to support multiple parallel MCMC chains, with enhanced features that enable considerably faster and more reliable estimation compared to the earlier version of the algorithm. We consider also a hierarchical tree representation, from which a Bayesian model-averaged structure estimate can be extracted. The algorithm is implemented in a computer program that features a user-friendly interface and built-in graphics. The enhanced features are illustrated by analyses of simulated data and an extensive human molecular dataset. AVAILABILITY: Freely available at http://www.rni.helsinki.fi/~jic/bapspage.html.     

Quantitative Changes in Gimap3 and Gimap5 Expression Modify Mitochondrial DNA Segregation in Mice

Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment.     

Bayesian search of functionally divergent protein subgroups and their function specific residues

MOTIVATION: The rapid increase in the amount of protein sequence data has created a need for an automated identification of evolutionarily related subgroups from large datasets. The existing methods typically require a priori specification of the number of putative groups, which defines the resolution of the classification solution. RESULTS: We introduce a Bayesian model-based approach to simultaneous identification of evolutionary groups and conserved parts of the protein sequences. The model-based approach provides an intuitive and efficient way of determining the number of groups from the sequence data, in contrast to the ad hoc methods often exploited for similar purposes. Our model recognizes the areas in the sequences that are relevant for the clustering and regards other areas as noise. We have implemented the method using a fast stochastic optimization algorithm which yields a clustering associated with the estimated maximum posterior probability. The method has been shown to have high specificity and sensitivity in simulated and real clustering tasks. With real datasets the method also highlights the residues close to the active site. AVAILABILITY: Software 'kPax' is available at http://www.rni.helsinki.fi/jic/softa.html     

Bayesian modeling of recombination events in bacterial populations

Background  

We consider the discovery of recombinant segments jointly with their origins within multilocus DNA sequences from bacteria representing heterogeneous populations of fairly closely related species. The currently available methods for recombination detection capable of probabilistic characterization of uncertainty have a limited applicability in practice as the number of strains in a data set increases.     

Efficient Bayesian approach for multilocus association mapping including gene-gene interactions

Background  

Since the introduction of large-scale genotyping methods that can be utilized in genome-wide association (GWA) studies for deciphering complex diseases, statistical genetics has been posed with a tremendous challenge of how to most appropriately analyze such data. A plethora of advanced model-based methods for genetic mapping of traits has been available for more than 10 years in animal and plant breeding. However, most such methods are computationally intractable in the context of genome-wide studies. Therefore, it is hardly surprising that GWA analyses have in practice been dominated by simple statistical tests concerned with a single marker locus at a time, while the more advanced approaches have appeared only relatively recently in the biomedical and statistical literature.     

Naturally occurring human autoantibodies recognize a fetal brain antigen identified as microtubulus associated protein 1B

We have recently reported naturally occurring autoantibodies against a large fetal brain antigen (FBA). Now we describe the process of purification and identification of this particular FBA. The brains of newborn rabbits were solubilized and purified with preparative gel electrophoresis. The protein fractions were concentrated and desalted and the fractions were tested by a known positive serum. On membrane digestion of the FBA-band gave a twelve amino acid sequence that resulted in best identity score for mouse, rat and human microtubule-associated protein (MAP) 1B: a member of the microtubule-associated protein family. Monoclonal anti-MAP1B recognized a band in immunoblots of the brain homogenate and of the partially purified fractions with the same electrophoretic mobility as that recognized by a known anti-FBA positive serum. When adult rabbit brain was used as an antigen, the anti-MAP1B failed to recognize any bands on immunoblots. MAP lB has not been previously known as an autoantigen, even though many structural proteins of the neuronal cytoskeleton are known to be targets of naturally occurring autoantibodies. MAP 1B is a functionally important regulatory protein in the developing brain; thus autoantibodies against MAP1B may affect the normal development.     

Electrophoretic methods for fractionation of native and heat-denatured bovine beta-lactoglobulin

We have developed three electrophoretic methods for analytical and preparative separation of native and heat-denatured beta-lactoglobulin. The methods can be applied, e.g., to optimize dairy milk processing, especially in laboratories which are not provided with expensive column chromatographic instruments. The methods consist of native PAGE followed by electroelution. Consequently, the eluted proteins are in solution in a biologically active and native form, and can therefore be used immediately for further analyses. This revised version was published online in July 2006 with corrections to the Cover Date.     

Effects of Lactobacillus reuteri PTA 5289 and L. paracasei DSMZ16671 on the Adhesion and Biofilm Formation of Streptococcus mutans

Probiotics have decreased the counts of salivary mutans streptococci (MS) in clinical studies. The aim of this study was to compare the effects of Lactobacillus reuteri PTA 5289 and L. paracasei DSMZ16671 on the adhesion of a reference strain and a clinical isolate of Streptococcus mutans and on the counts of MS in a biofilm. The adhesion of S. mutans Ingbritt and the clinical isolate S. mutans 2366 to a smooth glass surface and saliva-coated hydroxyapatite (SHA) were studied in the presence of and without the lactobacilli. A three-species biofilm formed on saliva-coated hydroxyapatite discs was used in the biofilm experiments. The lactobacilli did not affect adhesion to the glass surface but interfered with binding to SHA. No effects of the lactobacilli were detected on the MS levels in the three-species biofilms. The results of the SHA binding experiments best reflected the results of the existing clinical studies.