线粒体DNA异常与消化道疾病的关系

线粒体DNA是存在于细胞核外的唯一的遗传物质，属于细胞质遗传。与核DNA相比，线粒体基因组具有分子小、结构简单、母体遗传等特点。线粒体病是由线粒体DNA异常所致，好发于肌肉、心脏和大脑，听觉器官、胰腺、肝脏及消化道也常有累及，此文就线粒体DNA异常与消化道疾病的关系进行综述。     

线粒体DNA异常与消化道疾病的关系

线粒体DNA是存在于细胞核外的唯一的遗传物质,属于细胞质遗传。与核DNA相比,线粒体基因组具有分子小、结构简单、母体遗传等特点。线粒体病是由线粒体DNA异常所致,好发于肌肉、心脏和大脑,听觉器官、胰腺、肝脏及消化道也常有累及,此文就线粒体DNA异常与消化道疾病的关系进行综述。     

常见DNA聚合酶γ基因突变和线粒体疾病

DNA聚合酶是细胞复制DNA的重要作用酶。DNA聚合酶γ（polγ）存在于人类线粒体中,它是线粒体DNA复制和修复所必须。DNA聚合酶γ基因（POLG）发生突变后会导致其编码的polγ功能发生改变,使线粒体DNA（mtD—NA）复制及线粒体氧化磷酸化等功能障碍,引起线粒体相关疾病。对这些突变位点及其与疾病关系的研究为线粒体疾病的发病机制及治疗等提供了线索。本文对一些POLG常见位点突变相关研究进行了综述。     

线粒体DNA与衰老

随着分子生物学技术在衰老领域的应用，线粒体ＤＮＡ在衰老中的作用越来越受到关注，本文就线粒体ＤＮＡ的结构，遗传特点，突变原因，突变特点，生物学效应加以综述。     

线粒体DNA与衰老

随着增龄生物体在形态结构、生理功能方面出现的一系列慢性、进行性、退化性变化 ,其中的一个重要特征是衰老时各组织线粒体氧化磷酸化 (OXPHOS)功能下降。关于衰老已有很多学说 ,包括氧自由基、凋亡、基因等学说。氧自由基学说认为衰老是自由基引起的组织随机毒害的结果 〔1〕。而有人认为细胞程序死亡对衰老起主动作用并引起特征性形态改变及衰老性生长停滞 ,衰老细胞的死亡实质上就是细胞凋亡〔2〕。线粒体是细胞的能量转换器 ,动物体 95 %的能量产生于此。线粒体受核 DNA(n DNA)和线粒体 DNA(mt DNA)双重控制 ,其中 mt DNA控制…     

结直肠癌线粒体DNA拷贝数与其微卫星不稳定关系的研究

目的 探讨结直肠癌(CRC)的线粒体DNA(mtDNA)拷贝数异常与临床指标及微卫星不稳定(MSI)的关系.方法 选取50例CRC及相应癌旁组织标本,分别提取基因组DNA.对非编码区微卫星位点进行测序;对线粒体ND1基因进行荧光定量PCR,进而计算出mtDNA拷贝数;然后与临床指标和非编码区MSI进行比较分析.结果 CRC组织的mtDNA平均拷贝数/细胞数为312±185,而相应的癌旁组织为525±125,前者显著低于后者(P<0.001).mtDNA拷贝数高低与非编码区MSI有明显相关性(P<0.001),与性别、年龄、病理分型、TNM分期无相关性(P>0.05).结论 CRC的mtDNA拷贝数明显降低,这种降低与线粒体的MSI相关.     

基因组拷贝数变异与原发性高血压

基因组拷贝数变异（CNVs）是基因组结构变异的重要组成部分,根据其发生的频率可分为常见型CNVs和罕见型CNVs.研究发现CNVs参与许多疾病的发生发展,如先天性心脏病、肿瘤、神经精神疾病等.近年来的研究数据表明CNVs亦参与原发性高血压发病过程.该文阐述CNVs的由来、与原发性高血压发病的关系及目前研究的局限性,有助于深入认识原发性高血压发病的遗传本质和机制.     

线粒体DNA突变与衰老及退行性疾病的关系

线粒体ＤＮＡ突变与生物衰老以及老年退行性疾病的发生，发展均密切相关，阐明线粒体ＤＮＡ突变的规律及其与衰老及老年退行性疾病的关系将为预防和诊治这些疾病提供分子水平的理论依据针在提高人类生命质量，延缓人类衰老的进程中起重要作用。     

线粒体DNA突变与衰老

衰老又称老化,通常是指在正常状况下生物发育成熟后,随年龄增加,自身功能减退,内环境稳定能力与应激能力下降,结构、组分逐步退行性改变,趋向死亡,不可逆转的现象[1].1956年,Harman首先提出来衰老的自由基假说,之后又提出人类衰老过程中线粒体DNA是自由基攻击的首要目标.19世纪80年代初Miquel等提出"细胞衰老学说",认为衰老是由于氧自由基攻击线粒体DNA引起的一个生物过程.1989年Linnane等提出线粒体衰老假说.随着时代的发展与科技的进步,人们越来越关注线粒体与衰老的关系,线粒体与衰老的关系也成为研究前沿.\     

肺癌与线粒体DNA遗传变异

肺癌是当今世界最常见的恶性肿瘤之一,也是对人类生存和健康构成极大威胁的恶性肿瘤之一。近年来,肺癌致死率高达22．7％,已取代肝癌成为我国致死率最高的肿瘤。如果不采取有效干预措施,肺癌的患病率及致死率将进一步增加,到2025年我国肺癌患者将达到100万人次。肺癌的病因及发病机制迄今尚未明确,目前公认吸烟是导致肺癌的主要危险因素之一,此外,     

RNA-mediated epigenetic regulation of DNA copy number

Increasing evidence suggests that parentally supplied RNA plays crucial roles during eukaryotic development. This epigenetic contribution may regulate gene expression from the earliest stages. Although present in a variety of eukaryotes, maternally inherited characters are especially prominent in ciliated protozoa, in which parental noncoding RNA molecules instruct whole-genome reorganization. This includes removal of nearly all noncoding DNA and sorting the remaining fragments, producing extremely gene-rich somatic genomes. Chromosome fragmentation and extensive replication produce variable DNA copy numbers in the somatic genome. Understanding the forces that drive and regulate copy number change is fundamental. We show that RNA molecules present in parental cells during sexual reproduction can regulate chromosome copy number in the developing nucleus of the ciliate Oxytricha. Experimentally induced changes in RNA abundance can both increase and decrease the levels of corresponding DNA molecules in progeny, demonstrating epigenetic inheritance of chromosome copy number. These results suggest that maternal RNA, in addition to controlling gene expression or DNA processing, can also program DNA amplification levels.     

Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets

AIM/HYPOTHESIS: Pancreatic beta cell function has been shown to decline with age in man. Depletion of mitochondrial DNA (mtDNA) copy number is associated with impaired insulin secretion in pancreatic beta cell lines, and decreased mtDNA copy number has been observed with age in skeletal muscle in man. We investigated whether mtDNA copy number decreases with age in human pancreatic beta cells, which might in turn contribute to the age-related decline in insulin secretory capacity. METHODS: We quantified mtDNA copy number in isolated human islet preparations from 15 pancreas donors aged between 17 and 75 years. Islets (n = 20) were individually hand-picked and pooled from each donor isolate for the quantification of mtDNA copy number and deleted mtDNA (%), which were determined using real-time PCR methods. RESULTS: There was a significant negative correlation between mtDNA copy number and islet donor age (r = -0.53, p = 0.044). mtDNA copy number was significantly decreased in islet preparations from donors aged > or =50 years (n = 8) compared with those aged <50 years (n = 7) (median [interquartile range]: 418 [236-503] vs 596 [554-729] mtDNA copy number/diploid genome; p = 0.032). None of the islet preparations harboured high levels of deleted mtDNA affecting the major arc. CONCLUSION/INTERPRETATION: Given the correlation between mtDNA content and respiratory chain activity, the age-related decrease in mtDNA copy number that we observed in human pancreatic islet preparations may contribute to the age-dependent decline in pancreatic beta cell insulin secretory capacity.     

DNA copy number alterations mark disease progression in paediatric chronic myeloid leukaemia

Early recognition of children with chronic phase chronic myeloid leukaemia (CML‐CP) at risk for developing a lymphoid blast crisis (LyBC) is desirable, because therapy options in CML‐LyBC are limited. We used Multiplex Ligation‐dependent Probe Amplification to determine whether B‐cell lymphoid leukaemia‐specific copy number alterations (CNAs) (e.g. IKZF1, PAX5, CDKN2A deletions) could be detected in CML‐CP and may be used to predict disease progression to LyBC. CNAs were detected in all patients with CML‐LyBC, but in none of the 77 patients with CML‐CP. Based on this study we conclude that CNAs remain a hallmark of disease progression.     

High-quality DNA sequence capture of 524 disease candidate genes

The accurate and complete selection of candidate genomic regions from a DNA sample before sequencing is critical in molecular diagnostics. Several recently developed technologies await substantial improvements in performance, cost, and multiplex sample processing. Here we present the utility of long padlock probes (LPPs) for targeted exon capture followed by array-based sequencing. We found that on average 92% of 5,471 exons from 524 nuclear-encoded mitochondrial genes were successfully amplified from genomic DNA from 63 individuals. Only 144 exons did not amplify in any sample due to high GC content. One LPP was sufficient to capture sequences from <100-500 bp in length and only a single-tube capture reaction and one microarray was required per sample. Our approach was highly reproducible and quick (<8 h) and detected DNA variants at high accuracy (false discovery rate 1%, false negative rate 3%) on the basis of known sample SNPs and Sanger sequence verification. In a patient with clinical and biochemical presentation of ornithine transcarbamylase (OTC) deficiency, we identified copy-number differences in the OTC gene at exon-level resolution. This shows the ability of LPPs to accurately preserve a sample's genome information and provides a cost-effective strategy to identify both single nucleotide changes and structural variants in targeted resequencing.     

Regulatory element copy number differences shape primate expression profiles

Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences. Additionally, we identified 127 CNDs that were processed pseudogenes and some of which were expressed. Furthermore, there were copy number-different regulatory regions such as ultraconserved elements and long intergenic noncoding RNAs with the potential to affect expression. We postulate that CNDs of these conserved sequences fine-tune developmental pathways by altering the levels of RNA.     

线粒体DNA与心肌病的关系

人类线粒体DNA（mtDNA）是细胞内唯一存在于细胞核外的遗传物质,参与了转录、编码2个rRNA,22个tRNA及线粒体呼吸链中的13种蛋白多肽亚单位。人类某些疾病与线粒体DNA缺陷有关。心肌病是一类原因不明的伴随心脏功能障碍的心肌疾病。研究显示,线粒体产生的大量活性氧可导致mtDNA缺失或突变,tRNA基因保守序列突变影响肌肉收缩蛋白合成,造成氧化磷酸化缺陷,影响能量代谢。因此,线粒体的功能缺陷可能在心肌病的发生发展中起一定的作用。本文探讨了mtDNA突变与心肌病的关系,对mtDNA的深入研究将为临床寻找病因以及预防、诊断、治疗心肌病提供新思路。