放射卫生

辐射对小鼠精子发生过程中印记基因表达的影响；bFGF基因在中子辐射肠道损伤和修复中的表达和意义；睡眠剥夺复合贫铀污染对大鼠行为学及皮层NOS的影响；γ射线照射人正常肝细胞染色体损伤的修复；辐照的血管内皮对造血干细胞迁徙的影响。[编者按]     

基因组印记与遗传疾病

经典的孟德尔遗传理论认为来自双亲的等位基因具有等同的遗传性,而且可以预测遗传性状在后代中的分离。但是在哺乳动物中,有一小部分基因仅有父源或母源的拷贝有功能,这种基于亲本来源的单等位基因表达的现象称为基因组印记(genom ic imprinting),这些单等位基因表达的基因称为印记基因(imprinting gene),印记基因在胚胎生长、行为发生、肿瘤生成、神经发育等过程中起着重要的作用,基因组印记的紊乱将导致一系列的疾病。1基因组印记基因组印记是一种不符合经典孟德尔理论的遗传现象,指配子或合子胚胎期染色体修饰,而产生的一种基于亲本来源…     

宫内发育迟缓对印记基因胰岛素样生长因子-2/过氧化物酶体增生物激活受体γ共激活因子1α基因表达的影响

目的研究新生儿胎盘组织中印记基因IGF-2和PGC-1α的甲基化和mRNA的表达水平,探讨印记基因与宫内发育迟缓的相关性。方法收集无妊娠期并发症及无胎盘脐带异常的足月儿新鲜胎盘共40例,其中正常出生体质量儿20例为对照组、足月小样儿20例为实验组,采用基因组DNA亚硫酸氢钠处理后直接测序法和实时荧光定量PCR方法检测以上标本中IGF-2和PGC-1α基因甲基化和mRNA的表达。结果实验组IGF-2和PGC-1α的基因甲基化的表达比对照组增高,mRNA表达水平较对照组降低,差异均有统计学意义(P0.05)。出生体质量与IGF-2和PGC-1αmRNA在胎盘中的表达呈正相关(r值分别为0.79、0.87,P0.01)。结论宫内发育迟缓影响印记基因IGF-2和PGC-1α的表达,这2个基因可能作为修饰的靶点,从而对宫内发育迟缓胎儿进行早期的干预。     

精子发生障碍的遗传学研究进展

不孕不育影响着约10%～15%的夫妇,其中男性因素约占一半。精子发生障碍是男性不育的主要病因,主要表现为无精子症或少弱精子症。大量研究已经确定Y染色体及Yq微缺失与男性不育的相关性。X染色体因其在男性仅有单拷贝而在精子生成过程中表达特殊,对精子发生障碍有重要意义。对畸精子症和弱精子症患者的研究表明,位于常染色体的4个基因（SPATA16,PICK1,CATSPER和AURKC）可能与精子发生障碍有关。虽然经全球范围的努力,预期在不久的将来可提供新的基因检测技术来检测精子发生障碍的遗传学原因,但目前可用于精子发生障碍的基因测试仍然有限。     

长链非编码LncRNA与雄性生殖初探

基因组计划的顺利完成和蛋白质组学及转录组学的蓬勃发展促进了RNA组学研究的日趋成熟。长链非编码RNA(Long noncoding RNA,LncRNA)是一类长度超过200nt非编码RNA,没有完整的开放阅读框,不具备编码蛋白质的能力。最近的研究表明,LncRNA参与基因印记、X染色体失活等机体内许多重要的生理过程。主要是通过DNA甲基化、组蛋白修饰、染色质重构等方式影响基因的表达。同时LncRNA在疾病的发生与发展过程中影响重大。近年来,通过二代测序技术以及基因芯片技术鉴定到lncRNA,其在精子发生过程中的独特作用也逐渐被学者们认知,但可参考基础实验的文献相对比较少,本文综述了lnc RNA的起源概述、作用机制和其在精子发生过程中调控机制的研究分析,旨在加深对生物体精子发生过程中调控性非编码RNA功能进一步认识,同时也能给生殖疾病的诊断、防治提供新的思路。     

印迹基因H19在早孕绒毛组织中印迹状态的研究

目的检测早孕绒毛组织中印迹基因H19印迹的状态,探讨其印迹状态与滋养细胞浸润能力之间的联系。方法PCR-RFLP方法检测93例正常早孕绒毛组织中H19的印迹状态。结果在93例正常早孕绒毛组织中,有42例为杂合子,杂合子基因型中有11例为双等位基因的表达,其中所有双等位基因表达均在孕5～9周,而孕10～12周未发现有双等位基因的表达。结论在早孕期间,H19基因在绒毛组织中存在双等位基因的表达,主要集中在孕10周前,提示H19基因在滋养细胞中可能存在有动态变化,并与滋养细胞的浸润能力的变化有一定的联系。     

遗传印迹或遗传印记(genetic imprinting)

最近一二十年来 ,人们观察到来自父源和母源的同源等位基因在子代中会表现出不同的活性 ,此即称为遗传印迹。因此 ,在某些疾病中 ,会因父源基因或母源基因活性的不同而使病情表现出严重或轻微。通常认为遗传印迹产生的原因是 :在生殖细胞形成过程中 ,ＤＮＡ甲基化修饰程度不同。高度甲基化被印迹的基因不表达和活性低 ,反之亦然。遗传印迹或遗传印记(genetic imprinting)@方福德!100005$北京市中国医学科学院基础医学研究所     

唐山地区汉族人群白细胞介素-6基因启动子-572C/G、-634C/G的多态性与脑梗死的研究

目的对患者白细胞介素-6(IL-6)、基因启动子-572C/G、基因启动子-634C/G在血清中的表达与脑梗死病情之间的关系针对地区性进行探讨。方法采用PCR-RFLP分析法对患者IL-6及对照组健康人群基因启动因子-572C/G、-634C/G检测,酶联免疫法检测IL-6血清表达水平。结果脑梗死患者血清中IL-6水平明显高于对照组,IL-6基因启动因子基因型频率与等位基因频率与对照组相比具有显著差异,通过基因频率风险分析得出脑梗塞G等位基因与C等位基因携带者风险相差1.6215倍,携带G等位基因患者血清中IL-6表达水平明显高于非携带者。结论基因启动子-572G/C与脑梗死发病具有相关性且可能为脑梗死发病的遗传易感基因,G等位基因个体通过促进IL-6表达增高而提高脑梗死患者各项风险。     

男性不育的遗传缺陷

男性不育主要表现为少精、无精。对该病遗传缺陷的研究已取得了不少进展,尤其是分子生物学技术的迅速发展使研究深入到了基因水平,可望揭示精子发生和男性不育的机制。就染色体异常和基因突变对精子发生的影响作一综述。     

环状RNA参与精子发生的研究进展北大核心CSCD

精子发生对成年雄性动物完成生育功能来说至关重要,这一复杂的生理过程需要相关基因适时适度的表达,大量的表观遗传调控因子参与其中,包括明星分子环状RNA。环状RNA具有表达丰富、进化保守、细胞或组织特异性以及更高的抗外切酶或核糖核酸酶降解能力等多种特征。它可以调控亲本基因的表达,作为mRNA陷阱、miRNA或蛋白质的海绵体来发挥作用,也可以通过结合RNA结合蛋白来参与精子的发生过程,包括生殖干细胞的形成、精子的形成、精浆的组成及睾丸组织的形成。本文就目前环状RNA参与精子发生的研究进展进行综述。     

Genomic imprinting and environmental disease susceptibility

Genomic imprinting is one of the most intriguing subtleties of modern genetics. The term "imprinting" refers to parent-of-origin-dependent gene expression. The presence of imprinted genes can cause cells with a full parental complement of functional autosomal genes to specifically express one allele but not the other, resulting in monoallelic expression of the imprinted loci. Genomic imprinting plays a critical role in fetal growth and behavioral development, and it is regulated by DNA methylation and chromatin structure. This paper summarizes the Genomic Imprinting and Environmental Disease Susceptibility Conference held 8-10 October 1998 at Duke University, Durham, North Carolina. The conference focused on the importance of genomic imprinting in determining susceptibility to environmentally induced diseases. Conference topics included rationales for imprinting: parental antagonism and speciation; methods for imprinted gene identification: allelic message display and monochromosomal mouse/human hybrids; properties of the imprinted gene cluster human 11p15.5 and mouse distal 7; the epigenetics of X-chromosome inactivation; variability in imprinting: imprint erasure, non-Mendelian inheritance ratios, and polymorphic imprinting; imprinting and behavior: genetics of bipolar disorder, imprinting in Turner syndrome, and imprinting in brain development and social behavior; and aberrant methylation: methylation and chromatin structure, methylation and estrogen exposure, methylation of tumor-suppressor genes, and cancer susceptibility. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter imprint gene expression and that can result in genetic diseases including cancer and behavioral disorders. Understanding the contribution of imprinting to the regulation of gene expression will be an important step in evaluating environmental influences on human health and disease.     

Model-based linkage analysis with imprinting for quantitative traits: ignoring imprinting effects can severely jeopardize detection of linkage

Genes with imprinting (parent-of-origin) effects express differently when inheriting from the mother or from the father. Some genes for development and behavior in mammals are known to be imprinted. We developed parametric linkage analysis that accounts for imprinting effects for continuous traits, implementing it in MORGAN. To study misspecification of imprinting on linkage analysis, we simulated eight markers over a 35 cM region with phenotypes where imprinting contributes 0, 25, 50, and 75% of the variance of a quantitative trait locus (QTL) effect and analyzed them under all four models. Multipoint lod scores were computed and maximized over the same 35 cM region. Our most important finding is the dramatic lod score improvement under the correct imprinting model over the no-imprinting model. For data with minor QTL allele frequency 0.05, the correct model provided the highest lod scores with maximum expected lod scores over 4 in all settings. Ignoring imprinting provided the lowest lod scores with maximum expected lod scores between -9.9 and 2.4. In the extreme scenario, cases with max lod > or =3 from the correct imprinting model and max lod < or =-2 from the no-imprinting model occurred in 86% of replications. Models with misspecified imprinting produced lod scores intermediate between those with correct imprinting and with no imprinting. The effects of model misspecification were less pronounced for singlepoint analysis. Our multipoint results illustrate that ignoring true imprinting severely impairs detection of linkage and erroneously excludes genomic regions (with max lod <-2), whereas accounting for it can substantially improve linkage detection.     

Affected-sib-pair test for linkage based on constraints for identical-by-descent distributions corresponding to disease models with imprinting

Holmans' possible triangle test for affected sib pairs has proven to be a powerful tool for linkage analysis. This test is a likelihood-ratio test for which maximization is restricted to the set of possible sharing probabilities. Here, we extend the possible triangle test to take into account genomic imprinting, which is also known as parent-of-origin effect. While the classical test without imprinting looks at whether affected sib pairs share 0, 1, or 2 alleles identical-by-descent, the likelihood-ratio test allowing for imprinting further distinguishes whether the sharing of exactly one allele is through the father or mother. Thus, if the disease gene is indeed subject to imprinting, the extended test presented here can take into account that affecteds will have inherited the mutant allele preferentially from one particular parent. We calculate the sharing probabilities at a marker locus linked to a disease susceptibility locus. Using our formulation, the constraints on these probabilities given by Dudoit and Speed ([1999] Statistics in Genetics; New York: Springer) can easily be verified. Next, we derive the asymptotic distribution of the restricted likelihood-ratio test statistic under the null hypothesis of no linkage, and give LOD-score criteria for various test sizes. We show, for various disease models, that the test allowing for imprinting has significantly higher power to detect linkage if imprinting is indeed present, at the cost of only a small reduction in power in case of no imprinting. Altogether, unlike many methods currently available, our novel model-free sib-pair test adequately models the epigenetic parent-of-origin effect, and will hopefully prove to be a useful tool for the genetic mapping of complex traits.     

子宫内膜异位症不孕的表观遗传学研究进展

子宫内膜异位症是生育年龄妇女不孕的主要原因之一,其机制仍不清楚.最新研究发现,子宫内膜异位症可能是一种表观遗传性疾病.DNA甲基化异常和印记功能紊乱是表现遗传异常的主要形式.在子宫内膜异位症中存在DNA的异常甲基化,这种异常甲基化与子宫内膜异位症不孕有关;印记基因对胎儿及胎盘的发育具有十分重要的作用,子宫内膜异位症相关的印记功能紊乱可能影响胚胎着床和发育.该文就DNA甲基化、基因印记与子宫内膜异位症不孕的研究进展作以综述,为子宫内膜异位症不孕新治疗方法的提出提供理论依据.     

The transmission disequilibrium test and imprinting effects test based on case-parent pairs

The transmission disequilibrium test (TDT) based on case-parents trios is a powerful tool in linkage analysis and association studies. When only one parent is available, the 1-TDT is applicable in the absence of imprinting. In the presence of imprinting, a statistic is proposed, based on case-mother pairs and case-father pairs to test for linkage when association is present as well as to test for association when linkage is present. The recombination fractions are allowed to be sex-specific in this test statistic. Meanwhile, a statistic based on case-parent pairs is proposed to test for imprinting. Both test statistics can be extended to include families with more than one affected offspring. A number of simulation studies are conducted to investigate the validity of the proposed tests. The effects of different ratios of the numbers of case-mother pairs and case-father pairs on the powers of the proposed tests are studied through simulation. The results show that the optimal ratio is 1:1. How to combine case-parents, case-mother pairs, and case-father pairs jointly in testing for linkage, association, and imprinting is addressed.     

Influence of epigenetic changes during oocyte growth on nuclear reprogramming after nuclear transfer

Genomic imprinting is the epigenetic mechanism that distinguishes whether the loci that are inherited from the maternal or paternal genome lead to parent-specific gene expression. The mechanism also regulates development in mammalian embryos. Genomic imprinting is established after implantation according to the specific markers that are imposed on the genome during gametogenesis; the allele-specific gene expression is then maintained throughout embryogenesis. The genomic imprinting markers are erased and renewed on an own-sex basis only in cells that differentiate into germline cells. This report shows that the epigenetic modifications that occur during oogenesis perform the crucial function of establishing the allele-specific expression of imprinted genes, and also suggests that the epigenetic DNA modification is related to the reprogramming and aberrant development seen in manipulated embryos.     

辅助生殖技术中基因印迹分析

人类辅助生殖临床数据已经显示,辅助生殖技术（ART）与自发流产、早产和围生期死亡、低体质量儿以及一些印迹疾病有关。在配子及胚胎早期发育过程中,基因印迹需经历印迹擦除、重建和维持过程,其中任何一个环节出错都可能导致胚胎发育缺陷,甚至死亡。ART恰施于这一表观遗传重编程的关键时期。因此,这些异常结局可能与ART导致的印迹基因的异常表达有关。而ART中主要的治疗手段有促排卵、体外受精、胞浆内单精子注射（ICSI）和体外培养。这些操作通过干扰基因印迹的重建和维持,影响基因表达和表型,进而影响配子和早期胚胎的发育,从而影响子代的生长发育潜能。     

Linkage Analysis of Asthma and Atopy Including Models with Genomic Imprinting

Asthma and atopy are two closely related, common complex traits in which a number of genetic and environmental factors are suspected to play a role. We have performed parametric and nonparametric multi‐marker linkage analysis for the Busselton data set, which is part of problem 1 of Genetic Analysis Workshop 12. In particular, we have focused on the dichotomous trait atopy, as well as on dichotomized versions of the quantitative traits RASTI and log_e slope. The lod score analysis with adequate modeling of a parent‐of‐origin effect, by use of the program GENEHUNTER‐IMPRINTING, was of special interest. The most prominent findings are a multipoint mod score of 3.12 at D13S153 for RASTI, and a multipoint mod score of 4.32 at the same locus for atopy, both with four‐penetrance imprinting models that point to a gene subject to maternal imprinting. In addition, there are marked differences between imprinting and non‐imprinting mod scores. These results corroborate earlier findings of linkage between atopy and D13S153, but add the aspect of paternal gene expression. Furthermore, suggestive evidence for linkage to atopy is found near D6S291, D7S530, and D14S74. The best‐fitting models for chromosome 6 and 14 may suggest that genomic imprinting takes place at these two loci as well. © 2001 Wiley‐Liss, Inc.     

Parent-of-origin, imprinting, mitochondrial, and X-linked effects in traits related to alcohol dependence: presentation Group 18 of Genetic Analysis Workshop 14

The participants of Presentation Group 18 of Genetic Analysis Workshop 14 analyzed the Collaborative Study on the Genetics of Alcoholism data set to investigate sex-specific effects for phenotypes related to alcohol dependence. In particular, the participants looked at imprinting (which is also known as parent-of-origin effect), differences between recombination fractions for the two sexes, and mitochondrial and X-chromosomal effects. Five of the seven groups employed newly developed or existing methods that take imprinting into account when testing for linkage, or test for imprinting itself. Single-marker and multipoint analyses were performed for microsatellite as well as single-nucleotide polymorphism markers, and several groups used a sex-specific genetic map in addition to a sex-averaged map. Evidence for paternal imprinting (i.e., maternal expression) was consistently obtained by at least two groups at genetic regions on chromosomes 10, 12, and 21 that possibly harbor genes responsible for alcoholism. Evidence for maternal imprinting (which is equivalent to paternal expression) was consistently found at a locus on chromosome 11. Two groups applied extensions of variance components analysis that model a mitochondrial or X-chromosomal effect to latent class variables and electrophysiological traits employed in the diagnosis of alcoholism. The analysis, without using genetic markers, revealed mitochondrial or X-chromosomal effects for several of these traits. Accounting for sex-specific environmental variances appeared to be crucial for the identification of an X-chromosomal factor. In linkage analysis using marker data, modeling a mitochondrial variance component increased the linkage signals obtained for autosomal loci.     

乳腺癌中胰岛素样生长因子2印迹状态的研究

目的探讨乳腺癌中胰岛素样生长因子-2(IGF-2)的印迹状态与乳腺癌发生发展的关系。方法采用聚合酶链反应(PCR)和限制性片断长度多态性(RFLP)的方法,在47例乳腺癌组织中筛选IGF-2杂合标本,并用逆转录PCR-RFLP检测杂合标本IGF-2的印迹状态。结果在癌组织和癌旁组织中都发现了IGF2的印迹丢失,癌旁组织中IGF2的印迹丢失率(79.2%)比癌组织中的发生率(50.0%)高,两组的差异有统计学意义(P=0.035)。如果乳腺癌组织中发现有IGF-2印迹丢失,其对应的癌旁组织也发现了IGF-2的印迹丢失,但如果乳腺癌组织中为IGF-2印迹保持,则其对应的癌旁组织有的为IGF-2印迹保持,有的为IGF-2印迹丢失。结论IGF2的印迹丢失可能参与了乳腺癌的发展过程。