Research priorities for mitochondrial disorders: Current landscape and patient and professional views

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively-funded research designed by academics meets core needs of people with mitochondrial disorders and their clinicians. The Priority Setting Partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers, and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment, and psychological impact. Following the removal of 'answered questions' the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive 'Top Ten of unanswered research questions for primary mitochondrial disorders'. These Top Ten questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support; and optimal management of stroke-like episodes and fatigue

Research priorities for mitochondrial disorders: current landscape and patient and professional views

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively-funded research designed by academics meets core needs of people with mitochondrial disorders and their clinicians. The Priority Setting Partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers, and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment, and psychological impact. Following the removal of ‘answered questions’ the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive ‘Top Ten of unanswered research questions for primary mitochondrial disorders’. These Top Ten questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support; and optimal management of stroke-like episodes and fatigue

The GAAS Metagenomic Tool and Its Estimations of Viral and Microbial Average Genome Size in Four Major Biomes

Metagenomic studies characterize both the composition and diversity of uncultured viral and microbial communities. BLAST-based comparisons have typically been used for such analyses; however, sampling biases, high percentages of unknown sequences, and the use of arbitrary thresholds to find significant similarities can decrease the accuracy and validity of estimates. Here, we present Genome relative Abundance and Average Size (GAAS), a complete software package that provides improved estimates of community composition and average genome length for metagenomes in both textual and graphical formats. GAAS implements a novel methodology to control for sampling bias via length normalization, to adjust for multiple BLAST similarities by similarity weighting, and to select significant similarities using relative alignment lengths. In benchmark tests, the GAAS method was robust to both high percentages of unknown sequences and to variations in metagenomic sequence read lengths. Re-analysis of the Sargasso Sea virome using GAAS indicated that standard methodologies for metagenomic analysis may dramatically underestimate the abundance and importance of organisms with small genomes in environmental systems. Using GAAS, we conducted a meta-analysis of microbial and viral average genome lengths in over 150 metagenomes from four biomes to determine whether genome lengths vary consistently between and within biomes, and between microbial and viral communities from the same environment. Significant differences between biomes and within aquatic sub-biomes (oceans, hypersaline systems, freshwater, and microbialites) suggested that average genome length is a fundamental property of environments driven by factors at the sub-biome level. The behavior of paired viral and microbial metagenomes from the same environment indicated that microbial and viral average genome sizes are independent of each other, but indicative of community responses to stressors and environmental conditions

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead