人类基因组SNPs的研究现状及应用前景

基因组DNA是生物体各种生理、病理性状的物质基础,人类DNA序列变异约90%表现为单核苷酸多态性(singlenucleotidepolymorphisms,SNPs),这是一种常见的遗传变异类型,在人类基因组中广泛存在,被认为是人类疾病易感性和药物反应的决定性因素。本文主要介绍了SNPs的分类及特点、人类基因组SNPs的研究现状、SNPs在实践中的应用,以及SNPs在遗传作图、医药、遗传易感性、个体化医疗等方面的研究前景,并探讨了当前SNPs研究中存在的问题。     

“第一届灵长类动物模型学术论坛”在昆明成功举行

灵长类动物是人类的近亲,其组织结构、免疫、生理、代谢和生殖等方面与人类高度相似。作为人类的近亲,利用其创建的人类疾病模型,比其它模式动物能更好地复制人类传染性和非传染性疾病模型,并有效地模拟人类疾病的病理过程,使得其成为预临床实验研究人类疾病的最佳模式生物.同时,灵长类动物研究成果能直接转化为临床应用,更有效地预测新疫苗、新药和新诊断试     

可变剪接与疾病的生物信息学研究概况

可变剪接是真核基因转录后期的重要调控机制,它使得同一条蛋白质编码基因能够产生多种转录体,极大的扩展了遗传信息的应用.研究发现,可变剪接与人类疾病有着密切的联系.错误的剪接会导致疾病,增加疾病的易感性与病变程度,甚至直接导致癌变.现对可变剪接调控机制与疾病的生物信息学研究进展进行综述.     

DNA复制调控与人类重大疾病——我国生物医学科学中长期战略发展的一个方向

目前,人类正受到日益严重的癌症、心血管疾病、病毒感染、老年病和其它人类疾病的困扰。疾病的肆虐将导致社会危机、威胁人类文明,如非典型肺炎对我国和世界的袭击所带来的损失和震撼。因此,为了与人类疾病斗争,通过新的途径了解疾病发生机理和发现新的特效药物是极为必要的。其中之一就是ＤＮＡ复制调控与人类疾病的基础和应用研究。生命现象最本质的内容就是ＤＮＡ复制。从生命科学发展来说,“ＤＮＡ复制调控和人类疾病...     

HLA基因多态性与结核病遗传易感性的研究进展

随着人类基因组计划的完成和功能基因组学的研究的进展,多种结核病候选易感基因被发现,其中人类白细胞抗原（HLA）基因是主要的候选基因之一。HLA基因作为人类最复杂、最具多态性的遗传系统,其功能涉及到机体免疫的各个方面,不同个体对疾病易感性的差异在很大程度上是由遗传因素所决定的,因此HLA基因与某些免疫性疾病的相关性已经成为近年来研究的热点,国内外学者对不同种族的人群对结核分枝杆菌感染的易感性做了大量的研究,探讨HLA基因多态性与结核病遗传易感性的关系。本文对这方面的研究进展做一综述。     

细菌和病毒感染性疾病的基因易感性研究

随着一些已经绝迹的传染性疾病的重新出现以及新的病菌、病毒感染性疾病的流行,对人类感染性疾病致病机制的研究已得到人们的广泛重视,而疾病易感性……     

传染性疾病的遗传易感性

传染性疾病是威胁人类健康的主要疾病类型之一。传染病的发生、发展是致病微生物、宿主的遗传因素与环境相互作用的结果。大量以单核苷酸多态性（SNP）为遗传标记,基于家系或无关群体的连锁和关联分析,已绘制出传染性疾病易感性的基因图谱。目前易感性的研究主要集中在疟疾、获得性免疫缺陷综合征、乙肝和严重急性呼吸系统综合征等传染性疾病。     

小型猪在肾脏疾病研究中的应用

随着对小型猪研究的不断深入,其作为人类疾病模型的优势日益明显,在生物医学研究中的应用也日趋增多。比较解剖学和生理学研究表明,小型猪的诸多生物学特性均与人类极为相似,尤其在肾脏的解剖和功能方面几乎是人类的复制品,使其在复制肾脏疾病模型,研究疾病发病机制和评估治疗策略等中具有无可替代的作用。本文将综述小型猪作为疾病动物模型在肾脏疾病研究中的应用。     

我国参与全球人类基因组计划

我国参与全球人类基因组计划王钦南（国家自然科学基金委员会生命科学部１０００８３）人类基因组计划的目标是破译人类遗传信息,建立完整的遗传信息数据库,它是科学家长期以来梦寐以求的＂圣餐＂,将成为２１世纪生命科学的资源宝库,并将促进生物学不同领域如神经生物学、细胞生物学、发育生物学等的发展;医学也将从中获得极大好处,５千多种遗传性疾病和危害人类的恶性肿瘤、心血管病和其它遗传易感性多因子疾病可能由此得到预测、预防、早诊和治疗。由基因组计划发展起来的新技术、新策略也适于农业、工业和环境科学。     

运用系统论原理复制人类疾病动物模型

依据系统论的基本原理,人类疾病动物模型采用整体设计,统筹考虑模型与实验动物生物学特性方面的相似性、模型复制的重复性、可靠性、适用性、可控性、易行性和经济性等,以便模型复制的顺利开展。整体性原则应贯穿整个模型复制过程,使复制的模型具有科学性和实用性。模型复制要落实系统论的相关性原则,一个模型不是孤立的,动物的各系统、各器官、各分子之间是相互联系,人类和动物在生物学、解剖学、组织学、胚胎学、生理学、病理学等方面的相互联系,疾病的发生、发展是相互联系的,相关性原则为动物模型研究人类疾病提供了理论依据。动物模型在时间和空间上处于不断运动变化发展之中,在研究模型的过程中,要用动态的方法而不是静止的方法来研究动物模型,应根据疾病的特点,分成不同的阶段,结合动物的免疫功能、营养状况、疾病的发展、转归等采用不同的对策。模型的复制采用最优化原则,要求模型设计最优化,选用高质量的实验动物,减少动物使用数量,保护动物福利与伦理,最终实现模型评价体系的最优化。     

The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis

For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future.     

Genotypic vs. condition effects on parasite-driven rare advantage

Models and empirical studies of coevolution assume host resistance and parasite infectivity are genetically based. However, nongenetic physiological or environmental influences could alter host susceptibility even when the relationship is genetically based. In this experiment we examined the influence of host genotype, host condition at the time of infection (age and reproductive status), and their interaction on resistance of the freshwater snail Potamopyrgus antipodarum) to its dominant trematode parasite (Microphallus sp.). We used a laboratory infection experiment of a clonal snail population to determine the susceptibility of juveniles, brooding adult females, and nonbrooding adult females. We found a significant effect of both life-history state and clonal genotype on the prevalence of infection. However, the relative susceptibility of different clonal genotypes was not altered by condition; genotypes that were rare in the natural population were less infected than those that were common for each life-history state. These results suggest that although host condition affects susceptibility, it does not disrupt the specificity of the match between parasites and common clonal genotypes. Hence these findings support the Red Queen hypothesis for the maintenance of sex under genetically based host-parasite interactions.     

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models, in which the genetic background is homogeneous and environmental factors can be controlled, are therefore valuable in genetic dissection of multifactorial diseases. We are fortunate to have excellent animal models for both type 1 and type 2 diabetes--the nonobese diabetic (NOD) mouse and the Nagoya-Shibata-Yasuda (NSY) mouse, respectively. Congenic mapping of susceptibility genes for type 1 diabetes in the NOD mouse has revealed that susceptibility initially mapped as a single locus often consists of multiple components on the same chromosome, indicating the importance of congenic mapping in defining genes responsible for polygenic diseases. The NSY mouse is an inbred animal model of type 2 diabetes established from Jcl:ICR, from which the NOD mouse was also derived. We have recently mapped three major loci contributing to type 2 diabetes in the NSY mouse. Interestingly, support intervals where type 2 diabetes susceptibility genes were mapped in the NSY mouse overlapped the regions where type 1 diabetes susceptibility genes have been mapped in the NOD mouse. Although additional evidence is needed, it may be possible that some of the genes predisposing to diabetes are derived from a common ancestor contained in the original closed colony, contributing to type 1 diabetes in the NOD mouse and type 2 diabetes in the NSY mouse. Such genes, if they exist, will provide valuable information on etiological pathways common to both forms of diabetes, for the establishment of effective methods for prediction, prevention, and intervention in both type 1 and type 2 diabetes.     

Extrapolating Antifungal Animal Data to Humans—Is It Reliable?

This article aimed to review animal models of antifungals and identifies human literature to assess if the extrapolation of results is reliable. Animal studies have helped identify area under the concentration curve to minimum inhibitory concentration ratio targets for new drugs and formulations such as isavuconazole and delayed-release posaconazole that have translated to successful outcomes in humans. Models have also been influential in the identification of possible combination therapies for the treatment of aspergillosis, such as voriconazole and echinocandins. However, challenges are endured with animal models when it comes to replicating the pharmacokinetics of humans which has been exemplified with the newest itraconazole formulation. Additionally, animal models have displayed a survival benefit with the use of iron chelators and amphotericin for mucormycosis which was not demonstrated in humans. Animal models have been a staple in the development and optimization of antifungal agents. They afford the ability to investigate uncommon diseases, such as invasive fungal infections, that would otherwise take years and many resources to complete. Although there are many benefits of animal models, there are also shortcomings. This is why the reliability of extrapolating data from animal models to humans is often scrutinized.     

Evolutionary determinants of genetic variation in susceptibility to infectious diseases in humans

Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology.     

Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone

Women mount more vigorous antibody- and cell-mediated immune responses following either infection or vaccination than men. The incidence of most autoimmune diseases is also higher in women than in men; however, during pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period. Successful pregnancy requires that the female immune system tolerate the presence of a semi-allogeneic graft for 9 months. Oral contraceptive use can increase susceptibility to certain genital tract infections and sexually transmitted diseases in women. Moreover, treatment of mice and rats with female sex hormones is required to establish animal models of genital tract Chlamydia, Neisseria and Mycoplasma infection. This review describes what is currently known about the effects of the female sex hormones oestradiol and progesterone on innate and adaptive immune responses in order to provide a framework for understanding these sex differences. Data from both human and animal studies will be reviewed.     

Metagenomics and personalized medicine

The microbiome is a complex community of Bacteria, Archaea, Eukarya, and viruses that infect humans and live in our tissues. It contributes the majority of genetic information to our metagenome and, consequently, influences our resistance and susceptibility to diseases, especially common inflammatory diseases, such as type 1 diabetes, ulcerative colitis, and Crohn's disease. Here we discuss how host-gene-microbial interactions are major determinants for the development of these multifactorial chronic disorders and, thus, for the relationship between genotype and phenotype. We also explore how genome-wide association studies (GWAS) on autoimmune and inflammatory diseases are uncovering mechanism-based subtypes for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next-generation animal models and new therapeutic strategies for targeting personalized disease phenotypes.     

Reproductive skew, concessions and limited control

Models of reproductive skew in cooperative and eusocial societies suggest that dominants allow subordinates to breed to induce them to remain peaceably in the group. However, it is not yet clear how widely the assumptions of these models apply to animal societies, and many of the trends that they predict are consistent with the simpler suggestion that there is a struggle for reproduction between dominants and subordinates, whose outcome depends on the potential costs and benefits of the contest to both parties. Models of reproductive skew that incorporate contests of this kind and empirical studies that can discriminate clearly between reproductive concessions and failures of control are now needed.     

Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents

Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials. This review outlines the key components in animal infection models which have been used extensively in antibiotic discovery and development including PK/PD analyses.     

Immunosenescence and age-related viral diseases

Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing.Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly.Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process.Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity.However,it is unclear which of these defects are critical for impaired immune defense against infection.This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.