By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we ...identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10
). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Summary
Nitrification is a critical process for the balance of reduced and oxidized nitrogen pools in nature, linking mineralization to the nitrogen loss processes of denitrification and anammox. ...Recent studies indicate a significant contribution of ammonia‐oxidizing archaea (AOA) to nitrification. However, quantification of the relative contributions of AOA and ammonia‐oxidizing bacteria (AOB) to in situ ammonia oxidation remains challenging. We show here the production of nitric oxide (NO) by Nitrosopumilus maritimus SCM1. Activity of SCM1 was always associated with the release of NO with quasi‐steady state concentrations between 0.05 and 0.08 μM. NO production and metabolic activity were inhibited by the nitrogen free radical scavenger 2‐phenyl‐4,4,5,5,‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (PTIO). Comparison of marine and terrestrial AOB strains with SCM1 and the recently isolated marine AOA strain HCA1 demonstrated a differential sensitivity of AOB and AOA to PTIO and allylthiourea (ATU). Similar to the investigated AOA strains, bulk water column nitrification at coastal and open ocean sites with sub‐micromolar ammonia/ammonium concentrations was inhibited by PTIO and insensitive to ATU. These experiments support predictions from kinetic, molecular and biogeochemical studies, indicating that marine nitrification at low ammonia/ammonium concentrations is largely driven by archaea and suggest an important role of NO in the archaeal metabolism.
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent ...a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Ammonia-oxidizing archaea are ubiquitous in marine and terrestrial environments and now thought to be significant contributors to carbon and nitrogen cycling. The isolation of Candidatus ..."Nitrosopumilus maritimus" strain SCM1 provided the opportunity for linking its chemolithotrophic physiology with a genomic inventory of the globally distributed archaea. Here we report the 1,645,259-bp closed genome of strain SCM1, revealing highly copper-dependent systems for ammonia oxidation and electron transport that are distinctly different from known ammonia-oxidizing bacteria. Consistent with in situ isotopic studies of marine archaea, the genome sequence indicates N. maritimus grows autotrophically using a variant of the 3-hydroxypropionate/4-hydroxybutryrate pathway for carbon assimilation, while maintaining limited capacity for assimilation of organic carbon. This unique instance of archaeal biosynthesis of the osmoprotectant ectoine and an unprecedented enrichment of multicopper oxidases, thioredoxin-like proteins, and transcriptional regulators points to an organism responsive to environmental cues and adapted to handling reactive copper and nitrogen species that likely derive from its distinctive biochemistry. The conservation of N. maritimus gene content and organization within marine metagenomes indicates that the unique physiology of these specialized oligophiles may play a significant role in the biogeochemical cycles of carbon and nitrogen.
Archaeal ammonia oxidizers (AOAs) are increasingly recognized as prominent members of natural microbial assemblages. Evidence that links the presence of AOA with in situ ammonia oxidation activity is ...limited, and the abiotic factors that regulate the distribution of AOA natural assemblages are not well defined. We used quantitative PCR to enumerate amoA (encodes α-subunit of ammonia monooxygenase) abundances; AOA amoA gene copies greatly outnumbered ammonia-oxidizing bacteria and amoA transcripts were derived primarily from AOA throughout the water column of Hood Canal, Puget Sound, WA, USA. We generated a Michaelis-Menten kinetics curve for ammonia oxidation by the natural community and found that the measured Km of 98±14 nmol l(-1) was close to that for cultivated AOA representative Nitrosopumilus maritimus SCM1. Temperature did not have a significant effect on ammonia oxidation rates for incubation temperatures ranging from 8 to 20 °C, which is within the temperature range for depths of measurable ammonia oxidation at the site. This study provides substantial evidence, through both amoA gene copies and transcript abundances and the kinetics response, that AOA are the dominant active ammonia oxidizers in this marine environment. We propose that future ammonia oxidation experiments use a Km for the natural community to better constrain ammonia oxidation rates determined with the commonly used (15)NH4(+) dilution technique.
Evolutionary Dynamics of Plant R-Genes Bergelson, Joy; Kreitman, Martin; Stahl, Eli A. ...
Science (American Association for the Advancement of Science),
06/2001, Letnik:
292, Številka:
5525
Journal Article
Recenzirano
Plant R-genes involved in gene-for-gene interactions with pathogens are expected to undergo coevolutionary arms races in which plant specificity and pathogen virulence continually adapt in response ...to each other. Lending support to this idea, the solvent-exposed amino acid residues of leucine-rich repeats, a region of R-genes involved in recognizing pathogens, often evolve at unusually fast rates. But within-species polymorphism is also common in R-genes, implying that the adaptive substitution process is not simply one of successive selective sweeps. Here we document these features in available data and discuss them in light of the evolutionary dynamics they likely reflect.
Sickness insurance and workers' compensation systems decide on peoples' eligibility for benefits, and are commonly based on medical certificates and assessments of work ability. Systems differ in the ...extent to which they preserve clients' dignity and right to fair assessments. In this article, we define a new concept for studying interactions between individuals and systems: social insurance literacy, which concerns how well people understand the different procedures and regulations in social insurance systems, and how well systems communicate with clients in order to help them understand the system.
The concept was defined through a scoping literature review of related concepts, a conceptual re-analysis in relation to the social insurance field, and a following workshop.
Five related concepts were reviewed for definitions and operationalizations: health literacy, financial/economic literacy, legal capability/ability, social security literacy, and insurance literacy.
Social insurance literacy is defined as the extent to which individuals can obtain, understand and act on information in a social insurance system, related to the comprehensibility of the information provided by the system. This definition is rooted in theories from sociology, social medicine and public health. In the next step, a measure for the concept will be developed based on this review.
Implications for rehabilitation
Social insurance literacy is a new concept that is based on theories in sociology, social medicine and public health.
It provides conceptual orientation for analyzing factors that may influence different outcomes of peoples' contacts with social insurance systems.
The concept is of relevance for rehabilitation professionals since it focuses on how interactions between individuals and systems can influence the rehabilitation process.
The study will in the next step develop a measure of social insurance literacy which will have practical applications for rehabilitation professionals.
The co-evolutionary 'arms race' is a widely accepted model for the evolution of host-pathogen interactions. This model predicts that variation for disease resistance will be transient, and that host ...populations generally will be monomorphic at disease-resistance (R -gene) loci. However, plant populations show considerable polymorphism at R -gene loci involved in pathogen recognition. Here we have tested the arms-race model in Arabidopsis thaliana by analysing sequences flanking Rpm1, a gene conferring the ability to recognize Pseudomonas pathogens carrying AvrRpm1 orAvrB (ref. 3). We reject the arms-race hypothesis: resistance andsusceptibility alleles at this locus have co-existed for millions of years. To account for the age of alleles and the relative levels ofpolymorphism within allelic classes, we use coalescence theory to model the long-term accumulation of nucleotide polymorphism in the context of the short-term ecological dynamics of disease resistance. This analysis supports a 'trench warfare' hypothesis, inwhich advances and retreats of resistance-allele frequency maintain variation for disease resistance as a dynamic polymorphism,.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined ...approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio
biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene,
, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.
A detailed description of local population structure in Arabidopsis thaliana is presented, including an assessment of the genetic relatedness of individuals collected from the same field. A ...hierarchical sample of four individuals from 37 local populations, including North America, England, Eastern and Western Europe, and Asia, and a selection of ecotypes, were analysed for variation in Adh, ChiA, FAH1, F3H, Rpm1, Rps5, and five microsatellite loci. Twenty-eight of the 37 population samples contained individuals with identical multilocus haplotypes, 12 of which were fixed for a single haplotype. These monomorphic populations were evenly distributed over the species range. Only in North America did we find a single multilocus haplotype shared among different populations, perhaps indicating a continental founder event. Despite the occurrence of local inbreeding, a considerable amount of genetic variation was found segregating within and among local populations. A novel analysis of haplotype differences reveals that genetic differentiation occurs at every geographic scale in A. thaliana, where we find a surprising under-representation of recent migrants between local populations. This leads us to hypothesize that most dispersal between A. thaliana populations is by pollen rather than seed. Based on the structure of A. thaliana populations, it appears that regional groups of local populations may provide the most appropriate genetic material for linkage disequilibrium mapping of adaptive traits.
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