与血小板数量和体积相关联的基因组位点
血小板参与止血作用，血小板的数量和体积受到严格控制。对在超过65000人当中进行的全基因组关联研究的结果所作的这项“元分析”，识别出53个基因组位点，它们与血小板的数量和体积有可靠关联。这些位点优先与基因编码区域对应，其中很多都在一个“蛋白—蛋白”相互作用网络中。用斑马鱼和果蝇所做的功能实验表明，这些新发现的基因当中有11个编码血细胞形成过程的新颖调控因子。
New gene functions in megakaryopoiesis and platelet formation
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
文献链接：https://www.nature.com/nature/journal/v480/n7376/full/nature10659.html
生物钟对毛囊干细胞的控制
存在于小鼠皮肤中特定小环境中的表皮干细胞，可以确保皮肤的动态平衡得到高效维持。毛囊隆突中的干细胞负责毛囊再生和伤口愈合。它们产生一组异质性细胞——比如说这些细胞在其对内部和外部提示的反应能力方面就是异质性的。由Salvador Benitah及其同事进行的这项研究表明，生物钟通过调控毛囊隆突干细胞对其微环境的反应能力来控制它们的激发状态和异质性。这意味着，始终都会有一组“准备好了”的细胞来对激发刺激作出反应，同时防止该微环境内的所有干细胞都变得具有响应能力。表皮干细胞若受到扰动，会影响组织的长期平衡，并使组织容易生成肿瘤。
The circadian molecular clock creates epidermal stem cell heterogeneity
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
文献链接：https://www.nature.com/nature/journal/v480/n7376/full/nature10649.html
直接预测基因突变后果的方法
基因决定论的局限性在临床上（如双胞胎的相同基因损伤却会产生不相同的后果）和在实验室中（如突变即便是在同质化环境中也会在同基因的动物中产生不同效应）都早已明显表现出来了。从认为人们也许有可能预测不同表现型这样一个假设出发，Ben Lehner及其同事建立了一个直接预测发育中的动物的突变后果的方法。他们利用一种非侵入性的、基于荧光的方法来监测线虫胚胎发育过程中的基因表达，并回顾性地将各个胚胎中的分子噪音与各自成年个体中的表现型进行了比较。于是，他们便识别出了两个调控性补偿机制：一个出现在密切相关的基因中；另一个涉及伴护分子等普遍性调控因子。根据这些补偿的强度，可以预测每个动物个体的成年表现型。
Predicting mutation outcome from early stochastic variation in genetic interaction partners
Many mutations, including those that cause disease, only have a detrimental effect in a subset of individuals. The reasons for this are usually unknown, but may include additional genetic variation and environmental risk factors. However, phenotypic discordance remains even in the absence of genetic variation, for example between monozygotic twins, and incomplete penetrance of mutations is frequent in isogenic model organisms in homogeneous environments. Here we propose a model for incomplete penetrance based on genetic interaction networks. Using Caenorhabditis elegans as a model system, we identify two compensation mechanisms that vary among individuals and influence mutation outcome. First, feedback induction of an ancestral gene duplicate differs across individuals, with high expression masking the effects of a mutation. This supports the hypothesis that redundancy is maintained in genomes to buffer stochastic developmental failure. Second, during normal embryonic development we find that there is substantial variation in the induction of molecular chaperones such as Hsp90 (DAF-21). Chaperones act as promiscuous buffers of genetic variation and embryos with stronger induction of Hsp90 are less likely to be affected by an inherited mutation. Simultaneously quantifying the variation in these two independent responses allows the phenotypic outcome of a mutation to be more accurately predicted in individuals. Our model and methodology provide a framework for dissecting the causes of incomplete penetrance. Further, the results establish that inter-individual variation in both specific and more general buffering systems combine to determine the outcome inherited mutations in each individual.
文献链接：https://www.nature.com/nature/journal/v480/n7376/full/nature10665.html
