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探討大規(guī)?；蚪M研究

隨著新一代基因組測序技術的發(fā)展，近十年來大規(guī)?；蚪M測序研究越來越多，由此積累出了龐大的數據群。該文從以下三方面探討了大規(guī)?；蚪M研究中的大數據問題:全基因組關聯研究以及外顯子組測序研究中的顯著性檢驗，以及如何使研究更具有統(tǒng)計學意義;外顯子組突變研究對于理解和預測當前和未來人類疾病和進化的模式具有重要意義;基于基因的稀有突變研究，及其與已知疾病的風險存在的相關性。

論文鏈接:Sham P C，et al..Statistical power and significance testing in large-scale genetic studies.

Significance testing was developed as an objective method for summarizing statistical evidence for a hypothesis.It has been widely adopted in genetic studies，including genome-wide association studies and，more recently，exome sequencing studies.However，significance testing in both genome-wide and exome-wide studies must adopt stringent significance thresholds to allow multiple testing，and it is useful only when studies have adequate statistical power，which depends on the characteristics of the phenotype and the putative genetic variant，as well as the study design.Here，we review the principles and applications of significance testing and power calculation，including recently proposed gene-based tests for rare variants.

蜘蛛基因組幫助認識毒液和蜘蛛絲的生成

蜘蛛利用毒液和絲網來捕捉獵物，因此也成為控制昆蟲和害蟲種群數量的一個關鍵物種?？茖W家對非洲社會性絲絨蜘蛛Stegodyphus mimosarum和巴西白膝頭蜘蛛Acanthoscurria geniculate的基因組和轉錄組進行了測序，并對毒液和蛛絲蛋白進行了深度分析，識別出了在毒液內的毒素處理和激活中可能涉及的新蛋白，對毒液和蜘蛛絲的生成中所涉及的基因和蛋白的有了新認識。這些信息有可能被用來分別推進有關毒液和蜘蛛絲的藥理應用，并且還可能促進將這些絲蛋白用于生物材料應用的研究中。

論文鏈接:Sanggaard W K，et al..Spider genomes provide insight into composition and evolution of venom and silk.

Nature Communications，2014，5(3765):1－11.doi:10.1038/ncomms4765.

Abstract:Spiders are ecologically important predators with complex venom and extraordinarily tough silk that enables capture of large prey.Here we present the assembled genome of the social velvet spider and a draft assembly of the tarantula genome that represent two major taxonomic groups of spiders.The spider genomes are large with short exons and long introns，reminiscent of mammalian genomes.Phylogenetic analyses place spiders and ticks as sister groups supporting polyphyly of the Acari.Complex sets of venom and silk genes/proteins are identified.We find that venom genes evolved by sequential duplication，and that the toxic effect of venom is most likely activated by proteases present in the venom.The set of silk genes reveals a highly dynamic gene evolution，new types of silk genes and proteins，and a novel use of aciniform silk.These insights create new opportunities for pharmacological applications of venom and biomaterial applications of silk.

植物光敏色素家族的作用機制

所有植物的葉子中都存在“光敏色素”蛋白家族，它們檢測到光線的存在會告知細胞植物處于白天還是黑夜，在蔭涼處或是在太陽下。“光敏色素”蛋白家族控制了植物趨光生長以及通過光合作用固定更多二氧化碳的過程。通過光輻射，植物中的光敏色素蛋白結構發(fā)生改變，將一些信號傳遞給細胞。科學家們研究了材料來源相對豐富的細菌光敏蛋白，發(fā)現這種結構改變使得幾乎整個分子被重建，這一發(fā)現增進了對于光敏色素作用機制的了解。有可能促成一些新的策略，開發(fā)出能夠在少光的地方生長的、更為高效的作物。

論文鏈接:Takala H，et al..Signal amplification and transduction in phytochrome photosensors.

Nature，2014，509:245－248.doi:10.1038/nature13310.

Abstract:Sensory proteins must relay structural signals from the sensory site over large distances to regulatory output domains.Phytochromes are a major family of red-light-sensing kinases that control diverse cellular functions in plants，bacteria and fungi1，2，3，4，5，6，7，8，9.Bacterial phytochromes consist of a photosensory core and a carboxy-terminal regulatory domain10，11.Structures of photosensory cores are reported in the resting state12，13，14，15，16，17，18 and conformational responses to light activation have been proposed in the vicinity of the chromophore19，20，21，22，23.However，the structure of the signalling state and the mechanism of downstream signal relay through the photosensory core remain elusive.Here we report crystal and solution structures of the resting and activated states of the photosensory core of the bacteriophytochrome from Deinococcus radiodurans.The structures show an open and closed form of the dimeric protein for the activated and resting states，respectively.This nanometre-scale rearrangement is controlled by refolding of an evolutionarily conserved‘tongue’，which is in contact with the chromophore.The findings reveal an unusual mechanism in which atomic-scale conformational changes around the chromophore are first amplified into an ?ngstrom-scale distance change in the tongue，and further grow into a nanometre-scale conformational signal.The structural mechanism is a blueprint for understanding how phytochromes connect to the cellular signalling network.

揭開大豆果實不裂之謎

野大豆果實自然開裂，種子過早散落不利于收獲，同時也是造成大豆減產的主要原因。在漫長的選擇和馴化等農業(yè)活動中，這一性狀得到改變，產生了果實不裂的栽培大豆。研究人員針對栽培大豆果實裂莢抗性這一關鍵馴化性狀展開了全面而深入的研究，發(fā)現野大豆果實腹縫線處的纖維帽細胞的層數和胞壁厚度具有關鍵作用，并找到了胞壁厚度相關基因，以及控制這些基因的抑制子元件。這是一種全新的調控果實不裂的分子機制，有望應用于豆類作物的品種改良和分子育種。

論文鏈接:Dong Y，et al..Pod shattering resistance associated with domestication is mediated by a NAC gene in soybean.

Nature Communications，2014，5:3352.doi:10.1038/ncomms4352.

Abstract:Loss of seed dispersal is a key agronomical trait targeted by ancient human selection and has been regarded as a milestone of crop domestication.In this study，in the legume crop soybean Glycine max(L.)Merr.which provides vegetable oils and proteins for humans，we show that the key cellular feature of the shattering-resistant trait lies in the excessively lignified fibre cap cells(FCC)with the abscission layer unchanged in the pod ventral suture.We demonstrate that a NAC(NAM，ATAF1/2 and CUC2)gene SHATTERING1-5(SHAT1-5)functionally activates secondary wall biosynthesis and promotes the significant thickening of FCC secondary walls by expression at 15-fold the level of the wild allele，which is attributed to functional disruption of the upstream repressor.We show that strong artificial selection of SHAT1-5 has caused a severe selective sweep across ～116 kb on chromosome 16.This locus and regulation mechanism could be applicable to legume crop improvement.

遺傳變異如何影響代謝和復雜疾病

研究人員利用高通量代謝譜進行的全基因組關聯掃描分析，為遺傳變異如何影響代謝和復雜疾病提供了新的見解。研究將代謝相關分子與基因功能聯系起來，以了解常見復雜疾病相關的根本分子途徑。將基因與它們可能的底物或產物進行映射，并將其與多種疾病聯系起來，包括高血壓、心血管疾病和糖尿病。這些遺傳區(qū)域優(yōu)先地映射到當前藥物開發(fā)計劃靶定的基因上。因此，可用來來評估遺傳對藥物反應的影響，并評估現有藥物對一系列疾病的治療潛力。該研究開發(fā)的一種開放獲取的數據庫，將促進代謝性疾病的藥物發(fā)現和疾病相關生物學機制的研究。

論文鏈接:Shin S，et al..An atlas of genetic influences on human blood metabolites.

Nature Genetics，doi:10.1038/ng.2982.Published online:11 May，2014.

Abstract:Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease.Here we report the most comprehensive exploration of genetic loci influencing human metabolism thus far，comprising 7，824 adult individuals from 2 European population studies.We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity with more than 400 metabolites in human blood.We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information on gene expression，heritability and overlap with known loci for complex disorders，inborn errors of metabolism and pharmacological targets.We further developed a database and web-based resources for datamining and results visualization.Our findings provide new insights into the role of inherited variation in blood metabolic diversity and identify potential new opportunities for drug development and for understanding disease.

半乳凝素可直接對抗偽裝細菌

人體能產生一個稱為半乳凝素的蛋白質家族，它們能識別并殺死那些糖涂層非常類似于人體自身細胞的細菌。這些蛋白能夠從各種各樣的致病細菌中識別出糖類，并有可能被作為抗生素來治療某些感染。與抗體不同的是，半乳凝素可直接殺死細菌。研究者使用來自細菌表面的多糖涂布于載玻片上組成微陣列研究了這一現象。依靠該研究提供的方法，可以識別人類抗微生物多糖抗體的發(fā)育和年齡特異性差異，從而可以預測對疾病的易感性。

論文鏈接:Stowell S R，et al..Microbial glycan microarrays define key features of host-microbial interactions.

Nature Chemical Biology，doi:10.1038/nchembio.1525.Published online:11 May，2014.

Abstract:Genomic approaches continue to provide unprecedented insight into the microbiome，yet host immune interactions with diverse microbiota can be difficult to study.We therefore generated a microbial microarray containing defined antigens isolated from a broad range of microbial flora to examine adaptive and innate immunity.Serological studies with this microarray show that immunoglobulins from multiple mammalian species have unique patterns of reactivity，whereas exposure of animals to distinct microbes induces specific serological recognition.Although adaptive immunity exhibited plasticity toward microbial antigens，immunological tolerance limits reactivity toward self.We discovered that several innate immune galectins show specific recognition of microbes that express self-like antigens，leading to direct killing of a broad range of Gram-negative and Gram-positive microbes.Thus，host protection against microbes seems to represent a balance between adaptive and innate immunity to defend against evolving antigenic determinants while protecting against molecular mimicry.