TRAP1 chaperone protein mutations and autoinflammation.

We identified a consanguineous kindred, of three affected children with severe autoinflammation, resulting in the death of one sibling and allogeneic stem cell transplantation in the other two. All three were homozygous for p.S208C mutation; however, their phenotype was more severe than previously reported, prompting consideration of an oligogenic autoinflammation model.

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.

Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes.

TOPAZ: asymmetric suffix array neighbourhood search for massive protein databases.

Background: Protein homology search is an important, yet time-consuming, step in everything from protein annotation to metagenomics. Its application, however, has become increasingly challenging, due to the exponential growth of protein databases. In order to perform homology search at the required scale, many methods have been proposed as alternatives to BLAST that make an explicit trade-off between sensitivity and speed.

AAI-profiler: fast proteome-wide exploratory analysis reveals taxonomic identity, misclassification and contamination.

We present AAI-profiler, a web server for exploratory analysis and quality control in comparative genomics. AAI-profiler summarizes proteome-wide sequence search results to identify novel species, assess the need for taxonomic reclassification and detect multi-isolate and contaminated samples. AAI-profiler visualises results using a scatterplot that shows the Average Amino-acid Identity (AAI) from the query proteome to all similar species in the sequence database.

PANNZER2: a rapid functional annotation web server.

The unprecedented growth of high-throughput sequencing has led to an ever-widening annotation gap in protein databases. While computational prediction methods are available to make up the shortfall, a majority of public web servers are hindered by practical limitations and poor performance. Here, we introduce PANNZER2 (Protein ANNotation with Z-scoRE), a fast functional annotation web server that provides both Gene Ontology (GO) annotations and free text description predictions.

HaploForge: a comprehensive pedigree drawing and haplotype visualization web application.

Motivation: Haplotype reconstruction is an important tool for understanding the aetiology of human disease. Haplotyping infers the most likely phase of observed genotypes conditional on constraints imposed by the genotypes of other pedigree members. The results of haplotype reconstruction, when visualized appropriately, show which alleles are identical by descent despite the presence of untyped individuals.

Opportunities and challenges in metabarcoding approaches for helminth community identification in wild mammals.

Despite metabarcoding being widely used to analyse bacterial community composition, its application in parasitological research remains limited. What interest there has been has focused on previously intractable research settings where traditional methods are inappropriate, for example, in longitudinal studies and studies involving endangered species. In settings such as these, non-invasive sampling combined with metabarcoding can provide a fast and accurate assessment of component communities.

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1.

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right.

Robust multi-group gene set analysis with few replicates.

Background: Competitive gene set analysis is a standard exploratory tool for gene expression data. Permutation-based competitive gene set analysis methods are preferable to parametric ones because the latter make strong statistical assumptions which are not always met. For permutation-based methods, we permute samples, as opposed to genes, as doing so preserves the inter-gene correlation structure.

Wasabi: An Integrated Platform for Evolutionary Sequence Analysis and Data Visualization.

Wasabi is an open source, web-based environment for evolutionary sequence analysis. Wasabi visualizes sequence data together with a phylogenetic tree within a modern, user-friendly interface: The interface hides extraneous options, supports context sensitive menus, drag-and-drop editing, and displays additional information, such as ancestral sequences, associated with specific tree nodes. The Wasabi environment supports reproducibility by automatically storing intermediate analysis steps and includes built-in functions to share data between users and publish analysis results.

Tracking year-to-year changes in intestinal nematode communities of rufous mouse lemurs (Microcebus rufus).

While it is known that intestinal parasite communities vary in their composition over time, there is a lack of studies addressing how variation in component communities (between-hosts) manifests in infracommunities (within-host) during the host lifespan. In this study, we investigate the changes in the intestinal parasite infracommunities in wild-living rufous mouse lemurs (Microcebus rufus) from Ranomafana National Park in southeastern Madagascar from 2010 to 2012. We used high-throughput barcoding of the 18S rRNA gene to interrogate parasite community structure.

Séance: reference-based phylogenetic analysis for 18S rRNA studies.

Background: Marker gene studies often use short amplicons spanning one or more hypervariable regions from an rRNA gene to interrogate the community structure of uncultured environmental samples. Target regions are chosen for their discriminatory power, but the limited phylogenetic signal of short high-throughput sequencing reads precludes accurate phylogenetic analysis. This is particularly unfortunate in the study of microscopic eukaryotes where horizontal gene flow is limited and the rRNA gene is expected to accurately reflect the species phylogeny.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

Background/aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.

Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption).

Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy.

The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing.

Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.

SwiftLink: parallel MCMC linkage analysis using multicore CPU and GPU.

Motivation: Linkage analysis remains an important tool in elucidating the genetic component of disease and has become even more important with the advent of whole exome sequencing, enabling the user to focus on only those genomic regions co-segregating with Mendelian traits. Unfortunately, methods to perform multipoint linkage analysis scale poorly with either the number of markers or with the size of the pedigree. Large pedigrees with many markers can only be evaluated with Markov chain Monte Carlo (MCMC) methods that are slow to converge and, as no attempts have been made to exploit parallelism, massively underuse available processing power.

Genetic testing in renal disease.

A revolution is happening in genetics! The decoding of the first genome in 2003 was a large international collaborative effort that took about 13 years at a cost of around $2.7 billion. Now, only a few years later, new technology allows the sequencing of an entire genome within a few weeks--and at a cost of less than $10,000.

Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.

Background: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population.

Methods: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients).