应激与自杀、睡眠障碍的关系

自杀是复杂且致死率高的重要公共健康问题,应激和睡眠障碍均为自杀的重要风险因素,且三者之间具有密切的关联。由于应激和睡眠障碍具有可改变性,了解应激、睡眠和自杀的关系及其生理机制,有助于了解自杀的病理基础,探寻识别和干预自杀的关键靶点,促进对自杀的预防和干预。本文介绍有关应激、自杀、睡眠关联的最新研究结果,分别从 HPA轴功能、多胺应激反应系统等神经生理基础,以及基因、表观遗传修饰等遗传学的角度探讨三者关联的生理机制,探索该领域的研究挑战及未来的研究方向。     

我国科学家发现导致肥胖症新基因

正中国科学院遗传与发育生物学研究所李巍课题组领衔的研究发现,位于人类6号染色体长臂D6S1009位点旁侧的SLC35D3基因是人类肥胖症和代谢综合征的致病基因。相关研究于2013年2月13日发表于美国《科学公共图书馆—遗传学》。肥胖症的发生与遗传和环境两种因素有关,其中,遗传因素的贡献约占2/3。不过,研究人员虽已发现了一些单基因肥胖症的致病基因,如瘦素基因(LEP)等,还通过全基因组关联或连锁分析发现了150多个与肥胖症相关的基因位点,     

海洛因成瘾的遗传学研究进展

海洛因成瘾机制复杂多变,受遗传、环境、社会等多种因素影响,其中遗传因素是最重要的影响因素之一.随着遗传学研究方法的进展,人们发现除多巴胺能神经系统和单胺能神经系统相关基因外还有更多的基因多态性与海洛因成瘾易感性相关,本文就近年来新鉴定出的与海洛因成瘾相关的基因及其多态位点进行综述,以期为海洛因成瘾的机制研究以及成瘾标志...     

自杀行为候选基因5-HT2A受体基因的核酸及蛋白质分析

为阐明自杀行为的机制,在众多的自杀候选基因中,本文着重对候选基因5-HT2Α受体基因进行了生物信息学分析,结果支持候选基因及其编码蛋白质参与自杀行为的生理生化过程,为自杀行为受基因、环境的共同作用提供了间接证据,也为自杀行为机制的后续研究奠定了基础。     

体能相关基因研究的新进展

近年来体能与基因的关系又成为一个热点话题,人类遗传学的研究证实 ,人类体能的差异有遗传基础。 2000年以来,有关体能分子遗传学的研究飞速发展,发表的文章数及报道的相关基因座超过过去几年的总量,已经报到了70多个关注的基因座,证明基因与VO_2MAX、肌肉力量和乳酸阈值等有关。我国航空航天事业和载人航天器的开发、国防建设的需求等都提示,今后特殊体能人才的基因选材将不容忽视。对于具有特殊体能的个体进行科学选材,可以提高针对性和降低后期培养的资金浪费。同样,对于早期发现和培养具备体育运动天赋的人才将是经济快速和实用的方法。体能相关基因的研究还将为揭示这些基因座的功能、促进健康事业起重要作用。通过对国际已报道的主要与有氧运动相关的基因座和试验结果进行综述,为我国尽早开展相关研究提供基础信息。

     

人类身高的遗传学研究进展

人类身高是由环境和遗传因素共同决定的,遗传学研究发现遗传因素对身高差异的影响更大。身高是典型的多基因遗传性状,科研人员试图运用传统的连锁分析和关联分析寻找和发现对人类身高具有显著影响的常见DNA序列变异,但进展缓慢。近年来,随着基因分型和DNA测序技术的发展,人类身高的遗传学研究取得了很多突破性进展。全基因组关联分析(GWAS)的应用,发现和证实了上百个与人类身高相关的单核苷酸多态性位点(SNPs),拓展了人们对人类生长和发育的相关遗传学认识,同时也为研究人类其他复杂性状提供了理论依据和借鉴。本文综述了人类身高的遗传学研究进展,探讨了目前该研究领域所存在的问题和未来发展方向,以期为今后人类身高相关的遗传学研究提供参考和借鉴。     

心源性卒中的遗传学研究进展

心源性卒中是缺血性脑卒中的重要病因之一,表现出病情重、预后差和复发率高的特点。在遗传学研究中已经有相当多与心源性卒中相关的基因被鉴定,这些易感基因在疾病风险预测及危险因素评估的潜力也陆续被发掘。本文从全基因组关联研究、拷贝数变异研究、全基因组测序研究等方面综述了心源性卒中遗传学研究的相关进展,并介绍了其遗传数据集在多基因风险评分、孟德尔随机化的应用,旨在为将来深入研究心源性卒中的遗传发生机制提供借鉴和参考。     

酒精依赖相关基因的遗传多态性

酒精依赖综合征受到复杂的生理、心理、个体遗传及环境等诸多因素的影响。有关研究已经证实了某些候选基因和酒精依赖密切相关。文章主要对与酒精依赖相关的酒精代谢关键酶(乙醇脱氢酶和乙醛脱氢酶以及细胞色素P450 2E1)基因以及调节神经递质作用的酶和受体(儿茶酚氧位甲基转移酶, 多巴胺受体D2、D4, μ阿片受体)基因遗传多态性研究作一综述。     

DNA甲基化——肿瘤产生的一种表观遗传学机制

在人类基因组中,DNA甲基化是一种表观遗传修饰,它与肿瘤的发生关系密切。抑癌基因和DNA修复基因的高甲基化、重复序列DNA的低甲基化、某些印记基因的印记丢失与多种肿瘤的发生有关。目前研究发现,基因组中甲基化的水平不仅受DNA 甲基化转移酶（DNMT）的影响,还与组蛋白甲基化、叶酸摄入、RNA干扰等多种因素有关。DNA甲基化在基因转录过程中扮有重要角色,并与组蛋白修饰、染色质构型重塑共同参与转录调控。     

PARK 基因家族与帕金森病研究进展

帕金森病(Parkinson disease,PD)是一种多见于中老年人的神经系统变性疾病。PD的发病机制尚未完全清楚,绝大多数学者认为遗传缺陷、环境因素、老龄化等多种因素共同作用导致了PD的发生。近年来PD遗传学研究取得了长足的进步,确定了遗传因素在PD发病过程中的重要地位,发现并鉴定了多个与PD相关的基因。本文对相关基因的研究进展作一综述。     

Endophenotypes as a measure of suicidality

Suicide is thought to result from the harmful interaction of multiple factors that have social, environmental, neurobiological, and genetic backgrounds. Recent studies have suggested that genetic predisposition to suicidal behavior may be independent of the risk of suicide associated to mental disorders, such as affective disorders, schizophrenia, or alcohol dependence. Given the suicidal behavior heterogeneity and its hereditary complexity, the need to find demonstrable intermediate phenotypes that may make it possible to establish links between genes and suicide behaviors (endophenotypes) seems to be necessary. The main objective of this review was to consider the candidate endophenotypes of suicidal behaviors. Due to the recent advances in neuroimaging, we also characterize brain regions implicated in vulnerability to suicide behavior that are influenced by gene polymorphisms associated with suicidal behavior.     

A Genome-Wide Copy Number Variant Study of Suicidal Behavior

Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs) are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.     

Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses

Suicide is a major public health issue, especially in western countries, accounting for approximately 1 million deaths every year throughout the world. The tryptophan hydroxylase (TPH) gene has been extensively studied as a candidate for suicidal behavior due to its role in serotonergic neurotransmission. Since the first study associating the gene with schizophrenia, there have been many attempts to replicate it. However, a number of these studies have produced contrary results, possibly reflecting inadequate statistical power and the use of different populations. Association data relating European and, more particularly, Asian populations has become increasingly available in recent years. To examine whether the aggregate data provide evidence of statistical significance, the current meta-analysis has combined all the published studies up to July 2005, and examined the polymorphisms (A779C, A218C, A-6526G) in the context of varied suicidal behaviors by analyzing the studies in total and in subsets. Compared with the inconsistent results of previous studies, the current results (22 references) confirm a strong overall association between suicidal behavior and the A779C/A218C polymorphisms, supporting the involvement of TPH in the pathogenesis of suicidal behavior.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Association study of serotonin 2A receptor (5-HT2A) gene with schizophrenia and suicidal behavior using systematic meta-analysis

Serotonin 2A receptor (5-HT2A) gene was implicated to be associated with both schizophrenia and suicidal behavior due to its role of key neurotransmitter in many physiologic processes. Association studies were reported in different populations, however, a great number of subsequent studies have produced contrary results, possibly reflecting inadequate statistical power. With the cumulative data in recent years in both European and Asian populations, particularly in Asian populations, it was necessary to carry out a comprehensive analysis of previous findings. The meta-analysis, therefore, combined all English and Chinese studies using multiple research methods published up to July 2005 to give a new picture of the role of the 5-HT2A gene. Compared with significant results reported previously, the current large samples (73 studies in all) failed to find significant association of the T102C polymorphism with either schizophrenia or suicidal behavior. Evidence of significant association was only detected between A-1438G and suicidal behavior. The current study did not support the association of the 5-HT2A gene with either schizophrenia or suicidal behavior.     

Gene expression changes in the prefrontal cortex, anterior cingulate cortex and nucleus accumbens of mood disorders subjects that committed suicide

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.     

The use of non-metrical variations of the cranium in the study of Scandinavian population movements

The incidences of 30 non-metrical skull variants have been determined in 21 samples of crania from Scandinavia, Iceland and the British Isles. The samples have been compared to give Estimates of Divergence which are assumed to represent degrees of genetical affinity between them. In general these estimates are in accordance with known population movements in the area and also with genetical affinities determined from other systems. One bizarre result emphasizes the importance of caution in interpreting genetical distances found by this or similar methods. It is concluded that this method is a useful aid in human population studies.     

A genetical model for emergenesis: in memory of Laurence H. Snyder, 1901-86.

When a phenotype is determined by a specific gene combination of several loci, it is called an emergenic trait. Such a trait, although genetically controlled, does not usually run in families, since the specific gene combination can hardly be preserved in the process of reproduction. The present paper suggests a concrete genetical model to account for the phenomenon that there is little resemblance between siblings and parent-child pairs with respect to this trait. The genetical model is multiple homozygosis for all loci involved in the gene configuration. The properties of such a trait in a random mating population for all families, as well as for the segregating families only, are investigated. Some of the difficulties in estimating the genetical parameters on the basis of empirical data are also discussed.     

A new system of selecting yeast mutants with disrupted genetic recombination processes]

A new convenient system for isolation of the yeast mutants deficient in the genetical recombination is proposed. The chimeric plasmids constructed to carry the noncomplimenting mutant copy of the yeast ADE2 gene and different selectable yeast markers (LEU2 or TRP1 genes) are the basis for the system. Interplasmid intragenic recombination of ADE2 gene alleles in yeast cells transformed by two chimeric plasmids results in appearance of the secondary white prototrophic clones covering the primary red colony. The number of the clones reflects the recombination processes and is subject to an easy visual control. The proposed technique allows one to reveal both hypo and hyperrecombination mutants. Crossover or the gene conversion events can be distinguished by the simple genetical analysis of the secondary clones. The collection of mutants deficient in the genetical recombination has been obtained by the proposed technique.     

The relation between multilocus population genetics and social evolution theory

Evolution at multiple gene positions is complicated. Direct selection on one gene disturbs the evolutionary dynamics of associated genes. Recent years have seen the development of a multilocus methodology for modeling evolution at arbitrary numbers of gene positions with arbitrary dominance and epistatic relations, mode of inheritance, genetic linkage, and recombination. We show that the approach is conceptually analogous to social evolutionary methodology, which focuses on selection acting on associated individuals. In doing so, we (1) make explicit the links between the multilocus methodology and the foundations of social evolution theory, namely, Price's theorem and Hamilton's rule; (2) relate the multilocus approach to levels-of-selection and neighbor-modulated-fitness approaches in social evolution; (3) highlight the equivalence between genetical hitchhiking and kin selection; (4) demonstrate that the multilocus methodology allows for social evolutionary analyses involving coevolution of multiple traits and genetical associations between nonrelatives, including individuals of different species; (5) show that this methodology helps solve problems of dynamic sufficiency in social evolution theory; (6) form links between invasion criteria in multilocus systems and Hamilton's rule of kin selection; (7) illustrate the generality and exactness of Hamilton's rule, which has previously been described as an approximate, heuristic result.     

共表达PRRSV GP5蛋白和CSFV E2蛋白的“自杀性”DNA疫苗在小鼠体内诱导的免疫应答

为了获得新型双价"自杀性"DNA疫苗,将猪繁殖与呼吸综合征病毒(Porcine reproductive and respiratorysyndrome virus,PRRSV)GP5基因克隆于此前构建的表达猪瘟病毒(Classical swine fever virus,CSFV)E2基因的甲病毒复制子载体疫苗pSFV1CS-E2中.为了增强免疫效果,在密码子优化的GP5基因中插入了泛DR表位(PADRE),在CSFV E2基因后融合伪狂犬病病毒(PrV)UL49基因,获得了6种重组质粒.间接免疫荧光试验显示,PRRSV GP5和CSFV E2基因在瞬时转染的293T细胞中得到同时表达,将6种重组质粒和空载体pSFV1CS分别免疫BALB/c小鼠,用间接ELISA方法检测血清抗体水平,通过基于CSFE/WST-8的淋巴细胞增殖试验和细胞因子ELISA评价疫苗诱导的细胞免疫.结果显示,除pSFV1CS组外,从各疫苗组小鼠血清中均可检测到低水平的针对GP5和E2蛋白的抗体;各疫苗组小鼠脾细胞经CSFV和PRRSV刺激后均能诱导特异性的淋巴细胞增殖:部分疫苗组小鼠脾细胞经CSFV和PRRSV刺激后可分泌较高水平的IFN-γ和IL-4;引入UL49的疫苗组细胞免疫应答显著高于其它疫苗组.结果表明,这些共表达GP5和E2蛋白的自杀性DNA疫苗可以诱导体液免疫和细胞免疫,PrV UL49可以增强其细胞免疫应答.