抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

http://ggdpathway.wustl.edu/files/2014/08/ACMG-Guidelines-2015_Richards-et-al.pdf

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

We present here a framework for the study of molecular variation within a single species. Information on DNA haplotype divergence is incorporated into an analysis of variance format, derived from a matrix of squared-distances among all pairs of haplotypes. This analysis of molecular variance (AMOVA) produces estimates of variance components and F-statistic analogs, designated here as phi-statistics, reflecting the correlation of haplotypic diversity at different levels of hierarchical subdivision. The method is flexible enough to accommodate several alternative input matrices, corresponding to different types of molecular data, as well as different types of evolutionary assumptions, without modifying the basic structure of the analysis. The significance of the variance components and phi-statistics is tested using a permutational approach, eliminating the normality assumption that is conventional for analysis of variance but inappropriate for molecular data. Application of AMOVA to human mitochondrial DNA haplotype data shows that population subdivisions are better resolved when some measure of molecular differences among haplotypes is introduced into the analysis. At the intraspecific level, however, the additional information provided by knowing the exact phylogenetic relations among haplotypes or by a nonlinear translation of restriction-site change into nucleotide diversity does not significantly modify the inferred population genetic structure. Monte Carlo studies show that site sampling does not fundamentally affect the significance of the molecular variance components. The AMOVA treatment is easily extended in several different directions and it constitutes a coherent and flexible framework for the statistical analysis of molecular data.

/pdf/analysis-of-molecular-variance-inferred-from-metric-89hl32sg7j.pdf

Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data.

Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Significance Primary mitochondrial diseases (PMDs) are the most prevalent inborn metabolic disorders, affecting an estimated 1 in 4,200 individuals. Endurance exercise is generally known to improve mitochondrial function, but its indication in the heterogeneous group of PMDs is unclear. We determined the relationship between mitochondrial mutations, endurance exercise response, and the underlying molecular pathways in mice with distinct mitochondrial mutations. This revealed that mitochondria are crucial regulators of exercise capacity and exercise response. Endurance exercise proved to be mostly beneficial across the different mitochondrial mutant mice with the exception of a worsened dilated cardiomyopathy in ANT1-deficient mice. Thus, therapeutic exercises, especially in patients with PMDs, should take into account the physical and mitochondrial genetic status of the patient.

Mitochondrial mutations alter endurance exercise response and determinants in mice

Mechanisms of Mitochondrial Fission and Fusion Sumihiro Kawajiri Alexander M. van der Bliek, Qinfang Shen and Muscular Dystrophies Autophagy in the Pathogenesis of Collagen VI Mitochondrial Dysfunction and Defective Paolo Bernardi and Paolo Bonaldo Mitochondrial DNA into Cellular Homeostasis The Mitochondrial Nucleoid: Integrating al. Robert Gilkerson, Liliana Bravo, Iraselia Garcia, et Mitochondrial Disease -Related POLG Clinical and Molecular Features of Copeland Jeffrey D. Stumpf, Russell P. Saneto and William C.

Evolution and Disease Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in

This manuscript has been withdrawn by the authors due to disagreement with UCSF over data rights. This withdrawal decision is not related to the validity of the data presented in this study, and these authors understand that this work cannot be cited as reference for the project until the disagreement is resolved.

The principal mitochondrial K+ uniport is associated with respiratory complex I

Many T cell subsets have distinct metabolic requirements. Activated CD4 helper and cytotoxic CD8 T cells require glycolysis for optimal function, whereas Foxp3+ T-regulatory (Treg) cells are thought to be dependent on oxidative phosphorylation. We questioned if Foxp3 is involved with re-programming T cell metabolism. We retrovirally transduced murine T cells with Foxp3 or empty vector (EV), and also cultured CD4 + Foxp3 − T cells from Foxp3 YFPcre mice under polarizing conditions with TGFβ to form induced Tregs, using YFP to track Foxp3 expression. Our analysis of FACS-sorted YFP + iTreg and YFP − non-iTreg showed that both iTreg and Foxp3-transduced T cells had significantly higher basal oxygen consumption rates than non-iTreg or EV transduced T cell controls (44.1±49% and 76.1±76.5%, respectively, p + iTreg showed increased protein expression of electron transport chain complexes, especially complex I, compared to YFP − non-iTreg. We found that mice deficient in ND6, a mitochondrial encoded gene of complex I, have deficient Treg function. Furthermore, 50 nM rotenone, a complex I inhibitor, could selectively inhibit Treg suppressive function without affecting Tconv cell proliferation. The effects of Foxp3 on Treg metabolism may be physiological important to enable Tregs operating in low glucose environments such as the tumor microenvironment, and could offer an opportunity for therapeutic immune modulation.

Douglas C. Wallace

Papers

Mitochondrial mutations alter endurance exercise response and determinants in mice

Evolution and Disease Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in

The principal mitochondrial K+ uniport is associated with respiratory complex I

Foxp3 controls oxidative phosphorylation in regulatory T cells

Mitochondrial disease genetic diagnostics