探討大規(guī)模基因組研究

隨著新一代基因組測(cè)序技術(shù)的發(fā)展，近十年來大規(guī)?；蚪M測(cè)序研究越來越多，由此積累出了龐大的數(shù)據(jù)群。該文從以下三方面探討了大規(guī)?；蚪M研究中的大數(shù)據(jù)問題:全基因組關(guān)聯(lián)研究以及外顯子組測(cè)序研究中的顯著性檢驗(yàn)，以及如何使研究更具有統(tǒng)計(jì)學(xué)意義;外顯子組突變研究對(duì)于理解和預(yù)測(cè)當(dāng)前和未來人類疾病和進(jìn)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(fēng)險(xiǎn)存在的相關(guān)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(rèn)識(shí)毒液和蜘蛛絲的生成

蜘蛛利用毒液和絲網(wǎng)來捕捉獵物，因此也成為控制昆蟲和害蟲種群數(shù)量的一個(gè)關(guān)鍵物種?？茖W(xué)家對(duì)非洲社會(huì)性絲絨蜘蛛Stegodyphus mimosarum和巴西白膝頭蜘蛛Acanthoscurria geniculate的基因組和轉(zhuǎn)錄組進(jìn)行了測(cè)序，并對(duì)毒液和蛛絲蛋白進(jìn)行了深度分析，識(shí)別出了在毒液內(nèi)的毒素處理和激活中可能涉及的新蛋白，對(duì)毒液和蜘蛛絲的生成中所涉及的基因和蛋白的有了新認(rèn)識(shí)。這些信息有可能被用來分別推進(jìn)有關(guān)毒液和蜘蛛絲的藥理應(yīng)用，并且還可能促進(jìn)將這些絲蛋白用于生物材料應(yīng)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(jī)制

所有植物的葉子中都存在“光敏色素”蛋白家族，它們檢測(cè)到光線的存在會(huì)告知細(xì)胞植物處于白天還是黑夜，在蔭涼處或是在太陽下?！肮饷羯亍钡鞍准易蹇刂屏酥参镖吂馍L(zhǎng)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(jié)構(gòu)發(fā)生改變，將一些信號(hào)傳遞給細(xì)胞?？茖W(xué)家們研究了材料來源相對(duì)豐富的細(xì)菌光敏蛋白，發(fā)現(xiàn)這種結(jié)構(gòu)改變使得幾乎整個(gè)分子被重建，這一發(fā)現(xiàn)增進(jìn)了對(duì)于光敏色素作用機(jī)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(zhǎng)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(shí)不裂之謎

野大豆果實(shí)自然開裂，種子過早散落不利于收獲，同時(shí)也是造成大豆減產(chǎn)的主要原因。在漫長(zhǎng)的選擇和馴化等農(nóng)業(yè)活動(dòng)中，這一性狀得到改變，產(chǎn)生了果實(shí)不裂的栽培大豆。研究人員針對(duì)栽培大豆果實(shí)裂莢抗性這一關(guān)鍵馴化性狀展開了全面而深入的研究，發(fā)現(xiàn)野大豆果實(shí)腹縫線處的纖維帽細(xì)胞的層數(shù)和胞壁厚度具有關(guān)鍵作用，并找到了胞壁厚度相關(guān)基因，以及控制這些基因的抑制子元件。這是一種全新的調(diào)控果實(shí)不裂的分子機(jī)制，有望應(yīng)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(fù)雜疾病

研究人員利用高通量代謝譜進(jìn)行的全基因組關(guān)聯(lián)掃描分析，為遺傳變異如何影響代謝和復(fù)雜疾病提供了新的見解。研究將代謝相關(guān)分子與基因功能聯(lián)系起來，以了解常見復(fù)雜疾病相關(guān)的根本分子途徑。將基因與它們可能的底物或產(chǎn)物進(jìn)行映射，并將其與多種疾病聯(lián)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(dāng)前藥物開發(fā)計(jì)劃靶定的基因上。因此，可用來來評(píng)估遺傳對(duì)藥物反應(yīng)的影響，并評(píng)估現(xiàn)有藥物對(duì)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(shù)據(jù)庫，將促進(jìn)代謝性疾病的藥物發(fā)現(xiàn)和疾病相關(guān)生物學(xué)機(jī)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(duì)抗偽裝細(xì)菌

人體能產(chǎn)生一個(gè)稱為半乳凝素的蛋白質(zhì)家族，它們能識(shí)別并殺死那些糖涂層非常類似于人體自身細(xì)胞的細(xì)菌。這些蛋白能夠從各種各樣的致病細(xì)菌中識(shí)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(xì)菌。研究者使用來自細(xì)菌表面的多糖涂布于載玻片上組成微陣列研究了這一現(xiàn)象。依靠該研究提供的方法，可以識(shí)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(yù)測(cè)對(duì)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.