The mitochondrial genome and human mitochondrial diseases

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying form those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype--phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.     

The structure of human mitochondrial DNA variation

Summary Restriction analysis of mitochondrial DNA (mtDNA) of 3065 humans from 62 geographic samples identified 149 haplotypes and 81 polymorphic sites. These data were used to test several aspects of the evolutionary past of the human species. A dendrogram depicting the genetic relatedness of all haplotypes shows that the native African populations have the greatest diversity and, consistent with evidence from a variety of sources, suggests an African origin for our species. The data also indicate that two individuals drawn, at random from the entire sample will differ at approximately 0.4% of their mtDNA nucleotide sites, which is somewhat higher than previous estimates. Human mtDNA also exhibits more interpopulation heterogeneity (G_ST=0.351±0.025) than does nuclear DNA (G_ST=0.12). Moreover, the virtual absence of intermediate levels of linkage disequilibrium between pairs of sites is consistent with the absence of genetic recombination and places constraints on the rate of mutation. Tests of the selective neutrality of mtDNA variation, including the Ewens-Watterson and Tajima tests, indicate a departure in the direction consistent with purifying selection, but this departure is more likely due to the rapid growth of the human population and the geographic heterogeneity of the variation. The lack of a good fit to neutrality poses problems for the estimation of times of coalescence from human mtDNA data.     

启动以细胞为基本功能单元的系统人类基因转录组研究

基因组学、分子生物学和细胞生物学等基础生命科学领域前沿的概念和技术都在高速形成和发展,这些领域和新概念、新技术的不断融合推动生命科学研究从一个生长点到又一个新的生长点。人类基因组研究将在未来的五到十年里,从以一个基因组为对象的研究进入到以每个体基因组为对象的研究。基因功能和功能相关性的研究也将进入到以细胞为单元的研究,转录组研究必将成为这一研究的基础和出发点。转录组研究包括转录组的构成、调控和与蛋白质组的关联等基本部分,以及在临床诊断和药物研发中的应用。在生理状态下,每一种细胞中基因的共有和特异功能最终构成物种的生长、发育和演化。在病理状态下,每一种细胞中基因的变异和失控最终导致器官、组织、乃至个体的衰亡。人类转录组研究是基因功能研究的最基本层次之一,作为基因产物的RNA和蛋白质在这个层次上的存在、变化、关联和在细胞间的差异构成转录组研究的基本内容。