Correlated evolution of nucleotide substitution rates and allelic variation in Mhc-DRB lineages of primates

<p>Abstract</p> <p>Background</p> <p>The major histocompatibility complex (MHC) is a key model of genetic polymorphism. Selection pressure by pathogens or other microevolutionary forces may result in a high rate of non-synonymous substitutions at the codons specifying the contact residues of the antigen binding sites (ABS), and the maintenance of extreme MHC allelic variation at the population/species level. Therefore, selection forces favouring MHC variability for any reason should cause a correlated evolution between substitution rates and allelic polymorphism. To investigate this prediction, we characterised nucleotide substitution rates and allelic polymorphism (i.e. the number of alleles detected in relation to the number of animals screened) of several <it>Mhc </it>class II <it>DRB </it>lineages in 46 primate species, and tested for a correlation between them.</p> <p>Results</p> <p>First, we demonstrate that species-specific and lineage-specific evolutionary constraints favour species- and lineage-dependent substitution rate at the codons specifying the ABS contact residues (i.e. certain species and lineages can be characterised by high substitution rate, while others have low rate). Second, we show that although the degree of the non-synonymous substitution rate at the ABS contact residues was systematically higher than the degree of the synonymous substitution rate, these estimates were strongly correlated when we controlled for species-specific and lineage-specific effects, and also for the fact that different studies relied on different sample size. Such relationships between substitution rates of different types could even be extended to the non-contact residues of the molecule. Third, we provide statistical evidence that increased substitution rate along a MHC gene may lead to allelic variation, as a high substitution rate can be observed in those lineages in which many alleles are maintained. Fourth, we show that the detected patterns were independent of phylogenetic constraints. When we used phylogenetic models that control for similarity between species, due to common descent, and focused on variations within a single lineage (<it>DRB1*03</it>), the positive relationship between different substitution rates and allelic polymorphisms was still robust. Finally, we found the same effects to emerge in the analyses that eliminated within-species variation in MHC traits by using strictly single population-level studies. However, in a set of contrasting analyses, in which we focused on the non-functional <it>DRB6 </it>locus, the correlation between substitution rates and allelic variation was not prevalent.</p> <p>Conclusion</p> <p>Our results indicate that positive selection for the generation of allelic polymorphism acting on the functional part of the protein has consequences for the nucleotide substitution rate along the whole exon 2 sequence of the <it>Mhc-DRB </it>gene. Additionally, we proved that an increased substitution rate can promote allelic variation within lineages. Consequently, the evolution of different characteristics of genetic polymorphism is not independent.</p

Is CRT Optimization Obsolete? A Referral Center's Experience

Background: Cardiac resynchronization therapy (CRT) is a well-established therapy for patients with heart failure (HF). However, 30% of HF patients do not show any improvement in clinical status after CRT implantation. In this study, we report our echocardiography-based CRT optimization methodology, in daily practice at our CRT referral center. Methods: We included 350 ambulatory patients, who were referred to our center for optimization after CRT implantation. A protocol-driven echocardiographic approach for adjusting mechanical dyssynchrony, whereby adjusting for ventriculoventricular (VV) delays with strain and atrioventricular (AV) delays with Doppler echocardiography was performed. We defined changes in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) classes as outcome variables in the evaluation of the CRT outcomes. Results: Optimization was obtained in 288 (82%) patients. VV and AV timings were adjusted to 61% and 51%, respectively. In 3%, biventricular pacing was turned off and in 3% left ventricular (LV) only pacing was programmed. The LVEF and NYHA class showed significant improvements in all patients who underwent CRT optimization. Conclusions: CRT optimization remains valuable in improving LVEF and functional status measured using the NYHA class in all patients receiving CRT devices.</p

Is CRT Optimization Obsolete? A Referral Center's Experience

Background: Cardiac resynchronization therapy (CRT) is a well-established therapy for patients with heart failure (HF). However, 30% of HF patients do not show any improvement in clinical status after CRT implantation. In this study, we report our echocardiography-based CRT optimization methodology, in daily practice at our CRT referral center. Methods: We included 350 ambulatory patients, who were referred to our center for optimization after CRT implantation. A protocol-driven echocardiographic approach for adjusting mechanical dyssynchrony, whereby adjusting for ventriculoventricular (VV) delays with strain and atrioventricular (AV) delays with Doppler echocardiography was performed. We defined changes in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) classes as outcome variables in the evaluation of the CRT outcomes. Results: Optimization was obtained in 288 (82%) patients. VV and AV timings were adjusted to 61% and 51%, respectively. In 3%, biventricular pacing was turned off and in 3% left ventricular (LV) only pacing was programmed. The LVEF and NYHA class showed significant improvements in all patients who underwent CRT optimization. Conclusions: CRT optimization remains valuable in improving LVEF and functional status measured using the NYHA class in all patients receiving CRT devices.</p

IPD-MHC 2.0:An improved inter-species database for the study of the major histocompatibility complex

The IPD-MHC Database project (http://www.ebi.ac.uk/ipd/mhc/) collects and expertly curates sequences of the major histocompatibility complex from non-human species and provides the infrastructure and tools to enable accurate analysis. Since the first release of the database in 2003, IPD-MHC has grown and currently hosts a number of specific sections, with more than 7000 alleles from 70 species, including non-human primates, canines, felines, equids, ovids, suids, bovins, salmonids and murids. These sequences are expertly curated and made publicly available through an open access website. The IPD-MHC Database is a key resource in its field, and this has led to an average of 1500 unique visitors and more than 5000 viewed pages per month. As the database has grown in size and complexity, it has created a number of challenges in maintaining and organizing information, particularly the need to standardize nomenclature and taxonomic classification, while incorporating new allele submissions. Here, we describe the latest database release, the IPD-MHC 2.0 and discuss planned developments. This release incorporates sequence updates and new tools that enhance database queries and improve the submission procedure by utilizing common tools that are able to handle the varied requirements of each MHC-group

The KIR repertoire of a West African chimpanzee population is characterized by limited gene, allele, and haplotype variation

IntroductionThe killer cell immunoglobulin-like receptors (KIR) play a pivotal role in modulating the NK cell responses, for instance, through interaction with major histocompatibility complex (MHC) class I molecules. Both gene systems map to different chromosomes but co-evolved during evolution. The human KIR gene family is characterized by abundant allelic polymorphism and copy number variation. In contrast, our knowledge of the KIR repertoire in chimpanzees is limited to 39 reported alleles, with no available population data. Only three genomic KIR region configurations have been mapped, and seventeen additional ones were deduced by genotyping.MethodsPreviously, we documented that the chimpanzee MHC class I repertoire has been skewed due to an ancient selective sweep. To understand the depth of the sweep, we set out to determine the full-length KIR transcriptome – in our MHC characterized pedigreed West African chimpanzee cohort – using SMRT sequencing (PacBio). In addition, the genomic organization of 14 KIR haplotypes was characterized by applying a Cas9-mediated enrichment approach in concert with long-read sequencing by Oxford Nanopore Technologies.ResultsIn the cohort, we discovered 35 undescribed and 15 already recorded Patr-KIR alleles, and a novel hybrid KIR gene. Some KIR transcripts are subject to evolutionary conserved alternative splicing events. A detailed insight on the KIR region dynamics (location and order of genes) was obtained, however, only five new KIR region configurations were detected. The population data allowed to investigate the distribution of the MHC-C1 and C2-epitope specificity of the inhibitory lineage III KIR repertoire, and appears to be skewed towards C2.DiscussionAlthough the KIR region is known to evolve fast, as observed in other primate species, our overall conclusion is that the genomic architecture and repertoire in West African chimpanzees exhibit only limited to moderate levels of variation. Hence, the ancient selective sweep that affected the chimpanzee MHC class I region may also have impacted the KIR system

Evaluation of IL-28B Polymorphisms and Serum IP-10 in Hepatitis C Infected Chimpanzees

In humans, clearance of hepatitis C virus (HCV) infection is associated with genetic variation near the IL-28B gene and the induction of interferon-stimulated genes, like IP-10. Also in chimpanzees spontaneous clearance of HCV is observed. To study whether similar correlations exist in these animals, a direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients was performed. All chimpanzees studied were monomorphic for the human IL-28B SNPs which are associated with spontaneous and treatment induced HCV clearance in humans. As a result, these particular SNPs cannot be used for clinical association studies in chimpanzees. Although these human SNPs were absent in chimpanzees, gene variation in this region was present however, no correlation was observed between different SNP-genotypes and HCV outcome. Strikingly, IP-10 levels in chimpanzees correlated with HCV-RNA load and γGT, while such correlations were not observed in humans. The correlation between IP-10, γGT and virus load in chimpanzees was not found in patients and may be due to the lack of lifestyle-related confounding factors in chimpanzees. Direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients in relation to HCV infection, illustrates that the IFN-pathways are important during HCV infection in both species. The Genbank EMBL accession numbers assigned to chimpanzees specific sequences near the IL-28B gene are HE599784 and HE599785

Dynamics of the QTc interval over a 24-h dose interval after start of intravenous ciprofloxacin or low-dose erythromycin administration in ICU patients

QTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in critically ill patients. Critically ill patients may be more vulnerable to developing QTc prolongation, as several risk factors can be present at the same time. Therefore, it is important to know the QTc-prolonging potential of these drugs in the intensive care unit (ICU) population. The aim of this study was to assess the dynamics of the QTc interval over a 24-hour dose interval during intravenous ciprofloxacin and low-dose erythromycin treatment. Therefore, an observational study was performed in ICU patients (>= 18 years) receiving ciprofloxacin 400 mg t.i.d. or erythromycin 100 mg b.i.d. intravenously. Continuous ECG data were collected from 2 h before to 24 h after the first administration. QT-analyses were performed using high-end holter software. The effect was determined with a two-sample t-test for clustered data on all QTc values. A linear mixed model by maximum likelihood was applied, for which QTc values were assessed for the available time intervals and therapy. No evident effect over time on therapy with ciprofloxacin and erythromycin was observed on QTc time. There was no significant difference (p = 0.22) in QTc values between the ciprofloxacin group (mean 393 ms) and ciprofloxacin control group (mean 386 ms). The erythromycin group (mean 405 ms) and erythromycin control group (mean 404 ms) neither showed a significant difference (p = 0.80). In 0.6% of the registrations (1.138 out of 198.270 samples) the duration of the QTc interval was longer than 500 ms. The index groups showed slightly more recorded QTc intervals over 500 ms. To conclude, this study could not identify differences in the QTc interval between the treatments analyzed.Clinical Pharmacy and Toxicolog

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

Aim:Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at &lt;= 35 years of age was performed.Materials and Methods:Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age &lt;= 35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data.Results:The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 x 10(-9)), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p &lt; 10(-5), including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 x 10(-8)).Conclusions:This study expands the set of known genetic loci for severe periodontitis with an age of onset &lt;= 35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

Aim:Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at &lt;= 35 years of age was performed.Materials and Methods:Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age &lt;= 35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data.Results:The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 x 10(-9)), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p &lt; 10(-5), including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 x 10(-8)).Conclusions:This study expands the set of known genetic loci for severe periodontitis with an age of onset &lt;= 35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health