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探讨大规模基因组研究

随着新一代基因组测序技术的发展，近十年来大规模基因组测序研究越来越多，由此积累出了庞大的数据群。该文从以下三方面探讨了大规模基因组研究中的大数据问题:全基因组关联研究以及外显子组测序研究中的显著性检验，以及如何使研究更具有统计学意义;外显子组突变研究对于理解和预测当前和未来人类疾病和进化的模式具有重要意义;基于基因的稀有突变研究，及其与已知疾病的风险存在的相关性。

论文链接: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.

蜘蛛基因组帮助认识毒液和蜘蛛丝的生成

蜘蛛利用毒液和丝网来捕捉猎物，因此也成为控制昆虫和害虫种群数量的一个关键物种。科学家对非洲社会性丝绒蜘蛛Stegodyphus mimosarum和巴西白膝头蜘蛛Acanthoscurria geniculate的基因组和转录组进行了测序，并对毒液和蛛丝蛋白进行了深度分析，识别出了在毒液内的毒素处理和激活中可能涉及的新蛋白，对毒液和蜘蛛丝的生成中所涉及的基因和蛋白的有了新认识。这些信息有可能被用来分别推进有关毒液和蜘蛛丝的药理应用，并且还可能促进将这些丝蛋白用于生物材料应用的研究中。

论文链接: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机制

所有植物的叶子中都存在“光敏色素”蛋白家族，它们检测到光线的存在会告知细胞植物处于白天还是黑夜，在荫凉处或是在太阳下。“光敏色素”蛋白家族控制了植物趋光生长以及通过光合作用固定更多二氧化碳的过程。通过光辐射，植物中的光敏色素蛋白结构发生改变，将一些信号传递给细胞。科学家们研究了材料来源相对丰富的细菌光敏蛋白，发现这种结构改变使得几乎整个分子被重建，这一发现增进了对于光敏色素作用机制的了解。有可能促成一些新的策略，开发出能够在少光的地方生长的、更为高效的作物。

论文链接: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 ångstrom-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.

揭开大豆果实不裂之谜

野大豆果实自然开裂，种子过早散落不利于收获，同时也是造成大豆减产的主要原因。在漫长的选择和驯化等农业活动中，这一性状得到改变，产生了果实不裂的栽培大豆。研究人员针对栽培大豆果实裂荚抗性这一关键驯化性状展开了全面而深入的研究，发现野大豆果实腹缝线处的纤维帽细胞的层数和胞壁厚度具有关键作用，并找到了胞壁厚度相关基因，以及控制这些基因的抑制子元件。这是一种全新的调控果实不裂的分子机制，有望应用于豆类作物的品种改良和分子育种。

论文链接: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.

遗传变异如何影响代谢和复杂疾病

研究人员利用高通量代谢谱进行的全基因组关联扫描分析，为遗传变异如何影响代谢和复杂疾病提供了新的见解。研究将代谢相关分子与基因功能联系起来，以了解常见复杂疾病相关的根本分子途径。将基因与它们可能的底物或产物进行映射，并将其与多种疾病联系起来，包括高血压、心血管疾病和糖尿病。这些遗传区域优先地映射到当前药物开发计划靶定的基因上。因此，可用来来评估遗传对药物反应的影响，并评估现有药物对一系列疾病的治疗潜力。该研究开发的一种开放获取的数据库，将促进代谢性疾病的药物发现和疾病相关生物学机制的研究。

论文链接: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.

半乳凝素可直接对抗伪装细菌

人体能产生一个称为半乳凝素的蛋白质家族，它们能识别并杀死那些糖涂层非常类似于人体自身细胞的细菌。这些蛋白能够从各种各样的致病细菌中识别出糖类，并有可能被作为抗生素来治疗某些感染。与抗体不同的是，半乳凝素可直接杀死细菌。研究者使用来自细菌表面的多糖涂布于载玻片上组成微阵列研究了这一现象。依靠该研究提供的方法，可以识别人类抗微生物多糖抗体的发育和年龄特异性差异，从而可以预测对疾病的易感性。

论文链接: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.