Population Genetics Identifies Challenges in Analyzing Rare Variants

Geneticists have, for years, understood the nature of genome‐wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next‐generation sequencing can dramatically impact the false‐positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases.     

Adaptation of the disector method to rare small organelles in TEM sections exemplified by counting synaptic bodies in the rat pineal gland

The disector is the only objective method for quantifying particles of variable size in a given volume. With this method, cell organelles are identified on adjacent sections, but only those present in one section are counted. When counting extremely rare structures in transmission electron microscope sections (physical disector), the usual procedure of counting on electron micrographs is limited for economic reasons (e.g. micrographs highly outnumbering the investigated structures). Hence, to apply this unbiased stereological method, a modification of the physical disector concerning 3 aspects has been developed. (1) The prerequisite of screening large corresponding tissue areas (here ∼65000 μm²) was fulfilled by examining tissue areas along the edges of ultrathin sections. (2) The size of the counting frame was determined by measuring the lengths of the section margins (minus a guard area) by means of a Morphomat. This value was multiplied by the width of the investigated tissue zone, corresponding to the diameter of the electron microscope viewing screen. (3) Disector counting was carried out simultaneously on both sections (bidirectional disector) to improve efficiency. In the present study tiny synaptic bodies (SBs) were quantitated by disector in a rat pineal gland, yielding ∼30 SBs/1000 μm³. By contrast, single section profile counts of SBs amounted to 90 SBs/20000 μm². Since the presently described adaptation of the disector is time-consuming, it is proposed to determine a proportion factor allowing to estimate number of structures per volume based on single section profile counts. This would decrease the evaluation time by more than 50%.     

特安瑞林(Treplorelin)的致突变与致畸作用的研究

特安瑞林（Ｔｒｅｐｌｏｒｅｌｉｎ）的致突变与致畸作用的研究陆其明（上海医科大学公共卫生学院，２０００３２）特安瑞林（Ｔｒｅｐｌｏｒｅｌｉｎ，Ｄ－Ｔｒｐ－６－ＬＨＲＨ）是一种用于治疗子宫肌瘤的新药，其药理作用能促进性腺激素释放，使子宫内膜脱落和子宫肌瘤...     

轻稀土与联吡啶和菲罗啉三元配合物的合成与表征

合成了稀土（Ｌｎ）与２，２－联吡啶（Ｌ１）、１，１０－菲罗啉（Ｌ２）的三元固态配合物。通过元素分析、ＩＲ谱、ＴＧＡ谱和摩尔电导等对该系列配合物进行了表征，实测结果与通式ＬｎＬ１Ｌ２Ｃｌ３·３Ｈ２Ｏ符合较好。抗菌试验表明，该系列配合物有较强的广谱抗菌作用。     

Genetic testing for inherited eye conditions in over 6,000 individuals through the eyeGENE network

Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross‐referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.     

稀土对大鼠胃粘膜抗氧化能力的影响

目的　探讨大鼠短期服用硝酸稀土对胃粘膜抗氧化能力的影响。方法　按分组给药 30d后检测胃粘膜超氧化物歧化酶 (SOD)和过氧化脂质 (LPO)含量。结果　硝酸稀土 2 .0mg/kg和混合稀土 0 .1mg/kg组SOD含量显著升高 ;硝酸稀土 2 0 .0mg/kg组LPO含量显著升高 ,混合稀土 2 .0mg/kg和 0 .1mg/kg组LPO显著降低。结论　短期口服 2 0 .0mg/kg硝酸稀土可促进胃粘膜内脂质过氧化过程 ,0 .1、2 .0mg/kg的硝酸稀土可增强胃粘膜抗氧化能力 ,并抑制脂质过氧化过程     

芦丁稀土配合物的合成及药效学初步研究

目的　探索芦丁与稀土元素配位前后药效学的变化。方法　采用小鼠扭体法和耳壳肿胀法对芦丁与稀土元素配位前后镇痛与抗炎作用进行比较。结果　与NS组比较,芦丁及其配合物可明显减少醋酸所致小鼠扭体次数( P <0 0 5或P <0 0 1);与芦丁组比较,其各配合物组的镇痛作用更强(P <0 0 1)。同样,与NS组比较,芦丁及其配合物对二甲苯引起的小鼠耳壳肿胀有明显的抗炎作用(P <0 0 5或P <0 0 1);而各配合物的抗炎作用又强于芦丁组(P <0 0 5或P <0 0 1)。结论　芦丁稀土配合物较芦丁的镇痛、抗炎作用明显增强。     

长期喂饮钇对子代大鼠免疫功能的影响

目的探讨长期摄入稀土Y3+对子代大鼠免疫功能的影响。方法40只Wistar大鼠,随机分为4组,分别喂饮钇浓度为0、0·534、53·4和5340mg/L的饮用水。6个月后,处死F1代大鼠,心脏取血,摘取胸腺、睥,称重;流式细胞仪测定T细胞亚群CD3、CD4、CD8百分率,计算CD4/CD8比值;ELISA试剂盒测定血清中IgG、IgM含量。结果饮水中稀土浓度为0·534mg/L时,IgM、IgG含量明显升高(P<0·05),其他指标无明显变化;浓度为53·4mg/L时,各指标无明显变化;浓度为5340mg/L时,大鼠的CD3、CD8、IgM、IgG含量显著降低(P<0·05),CD4/CD8比值显著提高(P<0·05),CD4无明显变化;各剂量组大鼠脏器指数亦无明显变化。结论长期喂饮钇对子代大鼠的细胞免疫和体液免疫均有一定的影响。