Phylodynamics and Dispersal of HRSV Entails Its Permanence in the General Population in between Yearly Outbreaks in Children

Background: Human respiratory syncytial virus (HRSV) is one of the major etiologic agents of respiratory tract infections among children worldwide. Methodology/Principal Findings: Here through a comprehensive analysis of the two major HRSV groups A and B (n = 1983) which comprise of several genotypes, we present a complex pattern of population dynamics of HRSV over a time period of 50 years (1956-2006). Circulation pattern of HRSV revealed a series of expansions and fluctuations of co-circulating lineages with a predominance of HRSVA. Positively selected amino acid substitutions of the G glycoprotein occurred upon population growth of GB3 with a 60-nucleotide insertion (GB3 Insert), while other genotypes acquired substitutions upon both population growth and decrease, thus possibly reflecting a role for immune selected epitopes in linkage to the traced substitution sites that may have important relevance for vaccine design. Analysis evidenced the co-circulation and predominance of distinct HRSV genotypes in Brazil and suggested a year-round presence of the virus. In Brazil, GA2 and GA5 were the main culprits of HRSV outbreaks until recently, when the GB3 Insert became highly prevalent. Using Bayesian methods, we determined the dispersal patterns of genotypes through several inferred migratory routes. Conclusions/Significance: Genotypes spread across continents and between neighboring areas. Crucially, genotypes also remained at any given region for extended periods, independent of seasonal outbreaks possibly maintained by re-infecting the general population.FAPESPFAPESP [Nu 00/4205-6

The Diverse Applications of Cladistic Analysis of Molecular Evolution, with Special Reference to Nested Clade Analysis

The genetic variation found in small regions of the genomes of many species can be arranged into haplotype trees that reflect the evolutionary genealogy of the DNA lineages found in that region and the accumulation of mutations on those lineages. This review demonstrates some of the many ways in which clades (branches) of haplotype trees have been applied in recent years, including the study of genotype/phenotype associations at candidate loci and in genome-wide association studies, the phylogeographic history of species, human evolution, the conservation of endangered species, and the identification of species

Apoptotic Engulfment Pathway and Schizophrenia

Background: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. Methodology/Principal Findings: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. Conclusions/Significance: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease. © 2009 Chen et al

Genetic association analysis of overlapping biological pathways in cardiovascular and Alzheimer disease

To gain insight into the importance of the genome for diseases, sequencing and genotyping efforts aim to identify the consequences of genetic variation on both a functional and population level. The task involves the fine-resolution mapping of biologically significant genes and regions discerned by linkage analysis. This thesis focuses on genetic variation in two candidate genes, AngiotensinConverting Enzyme (ACE) and ATP-Binding Cassette A1 (ABCA1) that are shown to potentially modify Alzheimer disease (AD) risk and related quantitative traits. AD is a disabling neurodegenerative disorder characterized by progressive memory loss that affects an increasing part of the aging population. Mutations in the Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2) have been described to cause the early-onset familial form of AD. However, the discovery of genes involved in sporadic late-onset AD has proven to be more difficult. Apolipoprotein-E (APOE) which mediates lipid and cholesterol metabolism is the only presently recognized susceptibility gene for sporadic AD. The Angiotensin-Converting Enzyme modulates not only blood pressure homeostasis but also the clearance of amyloid-beta (Abeta), the pathogenic hallmark of AD, making ACE an intriguing biological candidate for both AD and cardiovascular disease. Significant effects for markers in the promoter and 3'- regions were found upon AD risk and disease age-of-onset, consistent with the presence of allelic heterogeneity in this genomic region. A unique differential relationship between genotypes for AD and obesity/ myocardial infarction was explored. The emerging pattern is consistent with the biological role of the ACE protein, but highlights the difficulties of analyzing pleiotropic genes. Computational analysis suggested functionally important promoter and splice variants that may be contributing to trait variability. ATP-Binding Cassette AI facilitates cholesterol transport and regulates APOE levels in cells. The gene lies in proximity to an AD linkage peak on chromosome 9q, making ABCA1 both a biological and positional candidate. In four independent European populations, significant differences in genotype frequencies were found between cases and controls indicated by effects on disease risk. Correlations between quantitative traits related to disease progression complemented the data. To substantiate findings, cholesterol and metabolic traits were examined in a large cardiovascular disease population whereby significant association was determined only among smokers. The data highlight the importance of considering environmental factors that can modify genotype-phenotype relationships. Applying association analysis across many traits using large replicating samples brings us closer to elucidating patterns of individual variations in genes that contribute to human diseases

Epidemiology and population dynamics of HRSV in São Paulo.

<p>Bayesian skyline plots of HRSV genotypes prevalent in São Paulo (top) and seasonal distribution of HRSV cases in São Paulo during the 1995–2005 seasons are shown in the <i>x</i>-axis. GA1, GA3 GA7 and GB4 were excluded from the BSL analysis because of small sample size (n<10). The <i>y</i>-axis (on the left) represents a measure of relative genetic diversity presented as <i>Ne.g</i> reflecting the change in effective number of infections over time; where <i>g</i> is the average generation time. The <i>y</i>-axis (on the right) represents the number of samples in the study. (-) - Number of total samples collected during the period. (-) - Number of all HRSV positive cases identified with monoclonal antibodies and molecular characterization.</p