蜱螨线粒体基因组研究进展

蜱螨亚纲包括蜱类和螨类, 是节肢动物中物种多样性最高的类群之一。本文综述了当前已测序的28种蜱螨线粒体基因组的研究成果。概括起来, 蜱螨线粒体基因组具有以下特点： （1）大小变异显著, 其中柑橘全爪螨Panonychus citri线粒体基因组在目前已测节肢动物中最小（13 077 bp）; （2）一般碱基组成偏向A和T, 但6种蜱螨具有相反的GC-偏斜（正值）; （3）基因组的碱基组成及A+T富集区的位置、 长度和拷贝数等变异显著, 其中4种叶螨的A+T含量最高, 其A+T富集区在目前已测节肢动物中最短（44~57 bp）; （4）基因高度重排, 特别是真螨总目的种类, 但重排与高分类阶元无相关性; （5）真螨总目部分螨类的tRNA基因极度缩短, 不能形成经典的三叶草二级结构。作者建议要进一步测定更多蜱螨的线粒体基因组, 验证蜱螨非典型tRNA基因的生物学功能性, 分析蜱螨线粒体基因组的分子进化机制, 开展蜱螨线粒体转录组研究等。     

Mitochondrial regulation of epigenetics and its role in human diseases

Most pathogenic mitochondrial DNA (mtDNA) mutations induce defects in mitochondrial oxidative phosphorylation (OXPHOS). However, phenotypic effects of these mutations show a large degree of variation depending on the tissue affected. These differences are difficult to reconcile with OXPHOS as the sole pathogenic factor suggesting that additional mechanisms contribute to lack of genotype and clinical phenotype correlationship. An increasing number of studies have identified a possible effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction. In particular, these studies demonstrate reversible or irreversible changes in genomic DNA methylation profiles of the nuclear genome. Here we review how mitochondria damage checkpoint (mitocheckpoint) induces epigenetic changes in the nucleus. Persistent pathogenic mutations in mtDNA may also lead to epigenetic changes causing genomic instability in the nuclear genome. We propose that “mitocheckpoint” mediated epigenetic and genetic changes may play key roles in phenotypic variation related to mitochondrial diseases or host of human diseases in which mitochondrial defect plays a primary role.     

Mitochondrial regulation of epigenetics and its role in human diseases

Most pathogenic mitochondrial DNA (mtDNA) mutations induce defects in mitochondrial oxidative phosphorylation (OXPHOS). However, phenotypic effects of these mutations show a large degree of variation depending on the tissue affected. These differences are difficult to reconcile with OXPHOS as the sole pathogenic factor suggesting that additional mechanisms contribute to lack of genotype and clinical phenotype correlationship. An increasing number of studies have identified a possible effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction. In particular, these studies demonstrate reversible or irreversible changes in genomic DNA methylation profiles of the nuclear genome. Here we review how mitochondria damage checkpoint (mitocheckpoint) induces epigenetic changes in the nucleus. Persistent pathogenic mutations in mtDNA may also lead to epigenetic changes causing genomic instability in the nuclear genome. We propose that “mitocheckpoint” mediated epigenetic and genetic changes may play key roles in phenotypic variation related to mitochondrial diseases or host of human diseases in which mitochondrial defect plays a primary role.     

Intergenomic epistasis for fitness: within-population interactions between cytoplasmic and nuclear genes in Drosophila melanogaster

The symbiotic relationship between the mitochondrial and nuclear genomes coordinates metabolic energy production and is fundamental to life among eukaryotes. Consequently, there is potential for strong selection to shape interactions between these two genomes. Substantial research attention has focused on the possibility that within-population sequence polymorphism in mitochondrial DNA (mtDNA) is maintained by mitonuclear fitness interactions. Early theory predicted that selection will often eliminate mitochondrial polymorphisms. However, recent models demonstrate that intergenomic interactions can promote the maintenance of polymorphism, especially if the nuclear genes involved are linked to the X chromosome. Most empirical studies to date that have assessed cytonuclear fitness interactions have studied variation across populations and it is still unclear how general and strong such interactions are within populations. We experimentally tested for cytonuclear interactions within a laboratory population of Drosophila melanogaster using 25 randomly sampled cytoplasmic genomes, expressed in three different haploid nuclear genetic backgrounds, while eliminating confounding effects of intracellular bacteria (e.g., Wolbachia). We found sizable cytonuclear fitness interactions within this population and present limited evidence suggesting that these effects were sex specific. Moreover, the relative fitness of cytonuclear genotypes was environment specific. Sequencing of mtDNA (2752 bp) revealed polymorphism within the population, suggesting that the observed cytoplasmic genetic effects may be mitochondrial in origin.     

Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes

A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations.     

Proteomic approaches to study plant-pathogen interactions

The analysis of plant proteomes has drastically expanded in the last few years. Mass spectrometry technology, stains, software and progress in bioinformatics have made identification of proteins relatively easy. The assignment of proteins to particular organelles and the development of better algorithms to predict sub-cellular localization are examples of how proteomic studies are contributing to plant biology. Protein phosphorylation and degradation are also known to occur during plant defense signaling cascades. Despite the great potential to give contributions to the study of plant-pathogen interactions, only recently has the proteomic approach begun to be applied to this field. Biological variation and complexity in a situation involving two organisms in intimate contact are intrinsic challenges in this area, however, for proteomics studies yet, there is no substitute for in planta studies with pathogens, and ways to address these problems are discussed. Protein identification depends not only on mass spectrometry, but also on the existence of complete genome sequence databases for comparison. Although the number of completely sequenced genomes is constantly growing, only four plants have their genomes completely sequenced. Additionally, there are already a number of pathosystems where both partners in the interaction have genomes fully sequenced and where functional genomics tools are available. It is thus to be expected that great progress in understanding the biology of these pathosystems will be made over the next few years. Cheaper sequencing technologies should make protein identification in non-model species easier and the bottleneck in proteomic research should shift from unambiguous protein identification to determination of protein function.     

Studies of heterogeneous mitochondrial populations in a mouse cell line: the effects of selection for or against mitochondrial genomes that confer chloramphenicol resistance

A single nucleotide substitution in a highly conserved region of the mitochondrial genome of a mouse cell line confers both chloramphenicol resistance and an alteration to the recognition site for the endonuclease Eco RV. This has enabled a detailed study on the effects of selection on a mitochondrial population comprising initially both chloramphenicol-resistant and chloramphenicol-sensitive mitochondrial genomes. The mutation confers advantage to cells grown in the presence of chloramphenicol, but is apparently deleterious in its absence. Selection at the cellular level is sufficient to explain the results observed. Fixation, which results in cells having mitochondria of only a single type, is slow. It is probable, therefore, that mammalian oocyte mitochondria are derived from only a small number of progenitors. This would allow fixation of new mutations and explain the observed uniformity in mitochondrial genomes of the individual in the presence of extensive variation between different members of the population.     

Review and meta‐analysis of natural selection in mitochondrial complex I in metazoans

Variation in mitochondrial DNA is often assumed to be neutral and is used to construct the genealogical relationships among populations and species. However, if extant variation is the result of episodes of positive selection, these genealogies may be incorrect, although this information itself may provide biologically and evolutionary meaningful information. In fact, positive Darwinian selection has been detected in the mitochondrial‐encoded subunits that comprise complex I from diverse taxa with seemingly dissimilar bioenergetic life histories, but the functional implications of the selected sites are unknown. Complex I produces roughly 40% of the proton flux that is used to synthesize ATP from ADP, and a functional model based on the high‐resolution structure of complex I described a unique biomechanical apparatus for proton translocation. We reported positive selection at sites in this apparatus during the evolution of Pacific salmon, and it appeared this was also the case in published reports from other taxa, but a comparison among studies was difficult because different statistical tests were used to detect selection and oftentimes, specific sites were not reported. Here we review the literature of positive selection in mitochondrial genomes, the statistical tests used to detect selection, and the structural and functional models that are currently available to study the physiological implications of selection. We then search for signatures of positive selection among the coding mitochondrial genomes of 237 species with a common set of tests and verify that the ND5 subunit of complex I is a repeated target of positive Darwinian selection in diverse taxa. We propose a novel hypothesis to explain the results based on their bioenergetic life histories and provide a guide for laboratory and field studies to test this hypothesis.     

On the adaptive value of cytoplasmic genomes in plants

Is DNA variation maintained in organelle genomes selectively neutral? The answer to this question has important implications for many aspects of ecology and evolution. While traditionally the answer has been ‘yes’, recent studies in animals have shown that, on the contrary, mitochondrial DNA polymorphism is frequently adaptive. In plants, however, the neutrality assumption has not been strongly challenged. Here, we begin with a critical evaluation of arguments in favour of this long‐held view. We then discuss the latest empirical evidence for the opposing prediction that sequence variation in plant cytoplasmic genomes is frequently adaptive. While outstanding research progress is being made towards understanding this fundamental topic, we highlight the need for studies that combine information ranging from field experiments to physiology to molecular evolutionary biology. Such an interdisciplinary approach provides a means for determining the frequency, drivers and evolutionary significance of adaptive organelle DNA variation.     

石松类和蕨类植物质体基因组结构演化研究进展

近年来, 随着测序技术的发展, 石松类和蕨类植物的核基因组、质体基因组以及线粒体基因组研究发展迅速, 质体基因组研究工作更是呈爆发式增长。截至2019年3月1日, GenBank公布的石松类和蕨类植物的175个质体基因组中, 约3/4为最近两年新增。研究内容从早期对个别质体基因组结构和序列特征的简单报道, 逐渐发展到综合性的比较基因组学和系统发育基因组学研究。目前已发表的质体基因组覆盖了石松类和蕨类植物的所有目和大部分科, 这两大类群的质体基因组结构变异和系统发育的基本框架已逐渐清晰。这些研究为我们理解维管植物的早期演化提供了重要参考。本文对石松类和蕨类植物的质体基因组结构特征进行了系统梳理, 发现其结构变异主要包括大片段倒位、IR区边界变动、基因或内含子丢失等, 其中一些结构变异可作为较高分类阶元的共衍征。RNA编辑和长片段非编码序列插入普遍存在于石松类和蕨类植物的质体基因组中, 但其起源、演化机制和功能等仍不清楚。我们对质体基因组的应用、系统发育研究中质体和核基因组的优劣性, 以及系统发育基因组学的前景进行了评述。     

Genomic Targets of Positive Selection in Giant Mice from Gough Island

A key challenge in understanding how organisms adapt to their environments is to identify the mutations and genes that make it possible. By comparing patterns of sequence variation to neutral predictions across genomes, the targets of positive selection can be located. We applied this logic to house mice that invaded Gough Island (GI), an unusual population that shows phenotypic and ecological hallmarks of selection. We used massively parallel short-read sequencing to survey the genomes of 14 GI mice. We computed a set of summary statistics to capture diverse aspects of variation across these genome sequences, used approximate Bayesian computation to reconstruct a null demographic model, and then applied machine learning to estimate the posterior probability of positive selection in each region of the genome. Using a conservative threshold, 1,463 5-kb windows show strong evidence for positive selection in GI mice but not in a mainland reference population of German mice. Disproportionate shares of these selection windows contain genes that harbor derived nonsynonymous mutations with large frequency differences. Over-represented gene ontologies in selection windows emphasize neurological themes. Inspection of genomic regions harboring many selection windows with high posterior probabilities pointed to genes with known effects on exploratory behavior and body size as potential targets. Some genes in these regions contain candidate adaptive variants, including missense mutations and/or putative regulatory mutations. Our results provide a genomic portrait of adaptation to island conditions and position GI mice as a powerful system for understanding the genetic component of natural selection.     

The Mitochondrial Genome of Raphanus sativus and Gene Evolution of Cruciferous Mitochondrial Types

To explore the mitochondrial genes of the Cruciferae family, the mitochondrial genome of Raphanus sativus (sat) was sequenced and annotated. The circular mitochondrial genome of sat is 239,723 bp and includes 33 protein-coding genes, three rRNA genes and 17 tRNA genes. The mitochondrial genome also contains a pair of large repeat sequences 5.9 kb in length, which may mediate genome reorga-nization into two sub-genomic circles, with predicted sizes of 124.8 kb and 115.0 kb, respectively. Furthermore, gene evolution of mitochondrial genomes within the Cruciferae family was analyzed using sat mitochondrial type (mitotype), together with six other re-ported mitotypes. The cruciferous mitochondrial genomes have maintained almost the same set of functional genes. Compared with Cycas taitungensis (a representative gymnosperm), the mitochondrial genomes of the Cruciferae have lost nine protein-coding genes and seven mitochondrial-like tRNA genes, but acquired six chloroplast-like tRNAs. Among the Cruciferae, to maintain the same set of genes that are necessary for mitochondrial function, the exons of the genes have changed at the lowest rates, as indicated by the numbers of single nucleotide polymorphisms. The open reading frames (ORFs) of unknown function in the cruciferous genomes are not conserved. Evolutionary events, such as mutations, genome reorganizations and sequence insertions or deletions (indels), have resulted in the non- conserved ORFs in the cruciferous mitochondrial genomes, which is becoming significantly different among mitotypes. This work represents the first phylogenic explanation of the evolution of genes of known function in the Cruciferae family. It revealed significant variation in ORFs and the causes of such variation.     

Functional conservatism among Drosophila simulans flies experiencing different thermal regimes and mitochondrial DNA introgression

Drosophila simulans possesses three different mitochondrial haplotypes (siI, II and III) that are nonrandomly geographically subdivided with a 3% interhaplogroup variation. The aim of this study was to determine whether perturbation of mitochondrial metabolism and ROS management by temperature variation and mtDNA introgression would influence the development of aerobic capacity and the intensity of oxidative stress in D. simulans at different ages. Environmental temperature divergences during development had few impacts on metabolic capacities. Our data suggested strong functional conservatism of mitochondrial haplotypes between the D. simulans lines studied. This conservatism was expressed by the low divergences in either mitochondrial or ROS buffering enzyme activities, or even markers of ROS damage even after disruption of coevolved genomes. Disruption of coevolved mitochondrial and nuclear genomes through mtDNA introgression induced no clear divergence on metabolic phenotype at any state of development. Reduction of cytochrome c oxidase activity that was observed after introgression of one mitochondrial haplotype will require further investigation to delineate whether it is associated with any modification of mito-nuclear interactions.     

Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells

Recent studies have described the occurrence of chromosomal abnormalities and mitochondrial dysfunction in human stem/stromal cells (SCs), particularly after extensive passaging in vitro and/or expansion under low oxygen tensions. To deepen this knowledge we investigated the influence of hypoxia (2% O(2)) and prolonged passaging (>P10) of human bone marrow stromal cells (BMSCs) and adipose-derived stromal cells (ASCs) on the expression of genes involved in DNA repair and cell-cycle regulation pathways, as well as on the occurrence of microsatellite instability and changes in telomere length. Our results show that hypoxic conditions induce an immediate and concerted down-regulation of genes involved in DNA repair and damage response pathways (MLH1, RAD51, BRCA1, and Ku80), concomitantly with the occurrence of microsatellite instability while maintaining telomere length. We further searched for mutations occurring in the mitochondrial genome, and monitored changes in intracellular ATP content, membrane potential and mitochondrial DNA content. Hypoxia led to a simultaneous decrease in ATP content and in the number of mitochondrial genomes, whereas the opposite effect was observed after prolonged passaging. Moreover, we show that neither hypoxia nor prolonged passaging significantly affected the integrity of the mitochondrial genome. Ultimately, we present evidence on how hypoxia selectively impacts the cellular response of BMSCs and ASCs, thus pointing for the need to optimize oxygen tension according to the cell source.     

The crucial role of plant mitochondria in orchestrating drought tolerance

BACKGROUND: Around the world, the frequency and intensity of droughts is increasing as a result of global climate change, with important consequences for the growth and survival of agricultural and native plant species. Understanding how plants respond to water stress is thus crucial for predicting the impacts of climate change on the crop productivity and ecosystem functioning. In contrast to the large number of studies assessing drought impacts on photosynthesis, relatively little attention has been devoted to understanding how mitochondrial respiratory metabolism is altered under water stress conditions. SCOPE: This review provides an overview of the impacts of water stress on mitochondrial respiration (R), combining studies at the whole-plant, individual organ, cellular and organelle levels. To establish whether there are clear patterns in the response of in vivo R to water stress, a wide range of root, leaf and whole-plant studies are reviewed. It is shown that water stress almost always inhibits R in actively growing roots and whole plants. However, in fully expanded, mature leaves the response is more variable, with water stress reducing R in near two-thirds of reported studies, with most of the remainder showing no change. Only a few studies reported increases in leaf R under severe water stress conditions. The mechanisms responsible for these variable responses are discussed. Importantly, the fact is highlighted that irrespective of whether drought increases or decreases respiration, overall the changes in R are minor compared with the large decreases in photosynthetic carbon gain in response to drought. Based on recent work highlighting the link between chloroplast and mitochondrial functions in leaves, we propose a model by which mitochondrial R enables survival and rapid recovery of productivity under water stress conditions. Finally, the effects of water stress on mitochondrial function, protein abundance and overall metabolism are reviewed.     

Natural selection and the evolution of mtDNA-encoded peptides: evidence for intergenomic co-adaptation.

Mitochondrial DNA (mtDNA) variation is an important tool for the investigation of the population genetics of animal species. Recently, recognition of the role of mtDNA mutations in human disease has spurred increasing interest in the function and evolution of mtDNA and the 13 polypeptides it encodes. These proteins interact with a large number of peptides encoded in the nucleus to form the mitochondrial electron transport system (ETS). As the ETS is the primary energy generation system in aerobic metazoans, natural selection would be expected to favor mutations that enhance ETS function. Such mutations could occur in either the mitochondrial or nuclear genes encoding ETS proteins and would lead to positive intergenomic interactions, or co-adaptation. Direct evidence for intergenomic co-adaptation comes from functional studies of systems where nuclear-mitochondrial DNA combinations vary naturally or can be manipulated experimentally.     

Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype

Background

Disorders of the mitochondrial respiratory chain are heterogeneous in their symptoms and underlying genetics. Simple links between candidate mutations and expression of disease phenotype typically do not exist. It thus remains unclear how the genetic variation in the mitochondrial genome contributes to the phenotypic expression of complex traits and disease phenotypes.

Scope of review

I summarize the basic genetic processes known to underpin mitochondrial disease. I highlight other plausible processes, drawn from the evolutionary biological literature, whose contribution to mitochondrial disease expression remains largely empirically unexplored. I highlight recent advances to the field, and discuss common-ground and -goals shared by researchers across medical and evolutionary domains.

Major conclusions

Mitochondrial genetic variance is linked to phenotypic variance across a variety of traits (e.g. reproductive function, life expectancy) fundamental to the upkeep of good health. Evolutionary theory predicts that mitochondrial genomes are destined to accumulate male-harming (but female-friendly) mutations, and this prediction has received proof-of-principle support. Furthermore, mitochondrial effects on the phenotype are typically manifested via interactions between mitochondrial and nuclear genes. Thus, whether a mitochondrial mutation is pathogenic in effect can depend on the nuclear genotype in which is it expressed.

General significance

Many disease phenotypes associated with OXPHOS malfunction might be determined by the outcomes of mitochondrial–nuclear interactions, and by the evolutionary forces that historically shaped mitochondrial DNA (mtDNA) sequences. Concepts and results drawn from the evolutionary sciences can have broad, but currently under-utilized, applicability to the medical sciences and provide new insights into understanding the complex genetics of mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.