封面故事: 严重肥胖和体重不足的病因可能互成镜像
体重不足和肥胖都会造成重要健康风险。但虽然肥胖已与若干种基因变异体联系在一起，而人们对体重不足的遗传基础却知之甚少。现在，对来自欧洲和北美28个细胞遗传中心的数据所做的一次大规模分析显示，体重不足经常与16号染色体上一个短的区域的复制相关。同一染色体区域的删除以前曾被与肥胖症联系在一起。所观察到的相关表现型与该位点基因删除的携带者中所报告的表现型是相对的或成镜像关系的，与该复制区域内的基因的转录水平的变化相关联，而不是与相邻区域内基因的转录水平的变化相关联。这表明，严重肥胖和体重不足可能有互成镜像的病因，并且可能是由能量平衡的相反效应造成的。
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m2 in adults and ≤ −2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ~600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
人卵细胞可将体细胞重新编程到多能状态
此前，人们一直没有可能做到利用人细胞通过体细胞核转移（实验室所采用的利用一个供体细胞核在其他哺乳动物体内生成一个卵细胞的成熟方法）实现体细胞核的重新编程及胚胎干(ES)细胞的衍生。但现在，Dieter Egli及其同事报告说，他们通过向人卵细胞中转移体细胞基因组，成功衍生出了三倍体人多能干细胞系。利用传统方法（先将卵细胞去核，然后将供体细胞融入其细胞核中）重构的人卵细胞在发育过程的解理阶段总会停止发育，但当卵细胞基因组没有被去掉、体细胞基因组被添加进去时，所得到的三倍体细胞会高效地发育到胚泡阶段。虽然这项研究尚未生成原始的、由“核转移”获得的二倍体ES细胞，但它却表明，这样的重新编程在人体中是有可能的。这项工作对于再生和生殖医学、发育生物学以及关于干细胞多能性的研究都是有意义的。它还提出了与无私供卵相关的有趣的伦理问题。George Daley 和 Jan Helge Solbakk在News & Views文章中、Insoo Hyun 和 Paul Tesar在Correspondence文章中都对这项研究工作在研究与伦理方面的问题进行了讨论。
Human oocytes reprogram somatic cells to a pluripotent state
The exchange of the oocyte’s genome with the genome of a somatic cell, followed by the derivation of pluripotent stem cells, could enable the generation of specific cells affected in degenerative human diseases. Such cells, carrying the patient’s genome, might be useful for cell replacement. Here we report that the development of human oocytes after genome exchange arrests at late cleavage stages in association with transcriptional abnormalities. In contrast, if the oocyte genome is not removed and the somatic cell genome is merely added, the resultant triploid cells develop to the blastocyst stage. Stem cell lines derived from these blastocysts differentiate into cell types of all three germ layers, and a pluripotent gene expression program is established on the genome derived from the somatic cell. This result demonstrates the feasibility of reprogramming human cells using oocytes and identifies removal of the oocyte genome as the primary cause of developmental failure after genome exchange.
RNA异常剪接对血液疾病的影响
研究人员对“脊髓发育不良”样本所做的外显子组测序和分析，在“RNA剪接机构”的多种组分中发现了经常性的、非重叠的改变，其中包括在U2AF35、ZRSR2、SRSF2和SF3B1中发生的突变。大多数受影响的基因在pre-mRNA处理过程中涉及3´-splice site的识别，被认为能引起异常RNA剪接和造血功能受损。这些结果显示了异常剪接在人类疾病发病过程中的作用。
Frequent pathway mutations of splicing machinery in myelodysplasia
Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (~45 to ~85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3′-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.
与“智障”相关的新基因
虽然与X-染色体相关的、早期发生的认知障碍（或称“智障”）的很多基因缺陷已被识别出来，但人们对其“常染色体隐性形式”的基因决定因素却了解很少。与前者相比，后者更为普遍。在一项试图对这种状况的分子基础有更多了解的系统性研究工作中，研究人员对患有这种状况的136个有血缘关系的家庭进行了“纯合性定位”、“外显子富集”和“下一代测序”。他们识别出了50个与“智障”相关的新的候选基因，同时也在以前被发现与神经疾病相关的几个基因中识别出了新的突变。这些新的候选基因中很多都与已知的“智障”基因产物发生相互作用，而且被预测会在对正常脑发育和功能至关重要的过程中发挥作用。
Deep sequencing reveals 50 novel genes for recessive cognitive disorders
Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.
用反义寡核苷酸治疗“福山型肌营养不良”的希望
“福山型肌营养不良”是由一个移动基因元素（SVA反转录转座子）向fukutin基因的非编码区域的插入引起的。Tatsushi Toda及其同事发现，这种插入会由于一个异常剪接事件（一种被称为“致病性外显子捕获”的情况）而将fukutin transcript截断。用反义寡核苷酸（它们能防止异常剪接）来处理肌营养不良小鼠模型的细胞或人类患者的细胞，可以恢复fukutin的功能。这些结果对于表现出“SVA外显子捕获”的其他疾病也有参考意义。
Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy
Fukuyama muscular dystrophy (FCMD; MIM253800), one of the most common autosomal recessive disorders in Japan, was the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposon into a causative gene. In FCMD, the SVA insertion occurs in the 3′ untranslated region (UTR) of the fukutin gene. The pathogenic mechanism for FCMD is unknown, and no effective clinical treatments exist. Here we show that aberrant messenger RNA (mRNA) splicing, induced by SVA exon-trapping, underlies the molecular pathogenesis of FCMD. Quantitative mRNA analysis pinpointed a region that was missing from transcripts in patients with FCMD. This region spans part of the 3′ end of the fukutin coding region, a proximal part of the 3′ UTR and the SVA insertion. Correspondingly, fukutin mRNA transcripts in patients with FCMD and SVA knock-in model mice were shorter than the expected length. Sequence analysis revealed an abnormal splicing event, provoked by a strong acceptor site in SVA and a rare alternative donor site in fukutin exon 10. The resulting product truncates the fukutin carboxy (C) terminus and adds 129 amino acids encoded by the SVA. Introduction of antisense oligonucleotides (AONs) targeting the splice acceptor, the predicted exonic splicing enhancer and the intronic splicing enhancer prevented pathogenic exon-trapping by SVA in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of α-dystroglycan (α-DG) and laminin binding by α-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia, neutral lipid storage disease ) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known we have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.
“老年性黄斑退化”的病因
“老年性黄斑退化”(AMD)是老年人失明的一个主要病因。“补体因子H” (CFH)的一个多态性已被与该疾病密切联系在一起，但这种联系的机制却不清楚。在这项研究中，研究人员发现，CFH专门与脂类过氧化反应产物丙二醛结合，后者由于氧化应激而在AMD疾病中积累。丙二醛和被丙二醛修饰的蛋白能诱导炎性反应，而CFH在试管中和在小鼠的视网膜中都能中和这种炎性潜力。 与AMD相关的一个常见的CFH多态性导致与丙二醛的结合受损，这有可能解释为什么有这一多态性的纯合子个体患该病的风险增加6-7倍。
Complement factor H binds malondialdehyde epitopes and protects from oxidative stress
Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.
基因对血压的影响
与其他常见的复杂疾病相比，实践证明，要确定血压升高的遗传基础特别困难。一项涉及20万欧洲裔人士的多阶段全基因组关联研究，填补了欧洲裔人士遗传知识中的一些空白。该研究识别出了16个相关位点，其中只有6个含有以前已知或被怀疑调控血压的基因。研究人员还在高血压、左心室壁厚度、中风和冠状动脉病之间发现了一个联系，但未发现与肾病或肾功能之间的联系。与来自超过7.5万东亚、南亚和非洲裔人士的数据所做比较证实，在欧洲裔研究对象中所识别出的变异体有很多还在其他族裔中影响血压。
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, GNAS–EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
