| 1. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Deans, Andrew R, et al.
(författare)
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Finding Our Way through Phenotypes.
- 2015
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
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| 3. |
- Wilson, Rachel M., et al.
(författare)
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Hydrogenation of organic matter as a terminal electron sink sustains high CO2 : CH4 production ratios during anaerobic decomposition
- 2017
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Ingår i: Organic Geochemistry. - : Elsevier BV. - 0146-6380 .- 1873-5290. ; 112, s. 22-32
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Tidskriftsartikel (refereegranskat)abstract
- Once inorganic electron acceptors are depleted, organic matter in anoxic environments decomposes by hydrolysis, fermentation, and methanogenesis, requiring syntrophic interactions between microorganisms to achieve energetic favorability. In this classic anaerobic food chain, methanogenesis represents the terminal electron accepting (TEA) process, ultimately producing equimolar CO2 and CH4 for each molecule of organic matter degraded. However, CO2:CH4 production in Sphagnum-derived, mineral-poor, cellulosic peat often substantially exceeds this 1:1 ratio, even in the absence of measureable inorganic TEAs. Since the oxidation state of C in both cellulose-derived organic matter and acetate is 0, and CO2 has an oxidation state of +4, if CH4 (oxidation state -4) is not produced in equal ratio, then some other compound(s) must balance CO2 production by receiving 4 electrons. Here we present evidence for ubiquitous hydrogenation of diverse unsaturated compounds that appear to serve as organic TEAs in peat, thereby providing the necessary electron balance to sustain CO2:CH4 > 1. While organic electron acceptors have previously been proposed to drive microbial respiration of organic matter through the reversible reduction of quinone moieties, the hydrogenation mechanism that we propose, by contrast, reduces CAC double bonds in organic matter thereby serving as (1) a terminal electron sink, (2) a mechanism for degrading complex unsaturated organic molecules, (3) a potential mechanism to regenerate electron-accepting quinones, and, in some cases, (4) a means to alleviate the toxicity of unsaturated aromatic acids. This mechanism for CO2 generation without concomitant CH4 production has the potential to regulate the global warming potential of peatlands by elevating CO2:CH4 production ratios.
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