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.

SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling. 

/pdf/setd2-inactivation-sensitizes-lung-adenocarcinoma-to-2nk1peog.pdf

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

Mitochondrial Genome, Overview

Publisher Summary This chapter examines some of the recent advances in mitochondrial genetics and the way in which they have altered our understanding of rare and common age-related diseases. Normal ATP generation by oxidative phosphorylation (OXPHOS) is a complex process requiring the coordinated expression of two genomes: (1) the nuclear DNA (nDNA) and (2) the mitochondrial DNA (mtDNA). OXPHOS is carried out by five enzyme complexes assembled from subunits encoded by the mtDNA. The first four complexes (I–IV) create the electron-transport chain which oxidizes electrons from NADH or FADH 2 and uses the energy to pump protons out of the mitochondrial inner membrane. This electrochemical gradient is utilized by Complex V to synthesize ATP from ADP+P i . The ATP is then exchanged across the mitochondrial inner membrane for cytosolic ADP by the adenine nucleotide translocator (ANT). The ANT and the catalytic ATP synthase β subunit share a muscle specific cis element, the OXBOX, which results in their coordinated elevated expression in heart and skeletal muscle. In addition to the 13 OXPHOS polypeptides, the mtDNA also encodes the rRNAs and tRNAs of mitochondrial protein synthesis.

Recent advances in mitochondrial genetics

Mitochondrially synthesized polypeptides of human, monkey, and mouse cells were compared using SDS-polyacylamide gel electrophoresis (SDS-PAGE). A single molecular weight variant, the major interspecific variant (MIV), was identified in human cells as compared to monkey and mouse. The peptide maps of MIV were compared between the three species using a two-dimensional proteolytic digest (2D-PD) gel system. A number of conserved peptides were found, indicating that the MIVs have a common function. Other MIV peptides were species specific. These results confirm the conserved nature of mitochondrial polypeptides and demonstrate the utility of 2D-PD gels in testing for protein alleles and detecting subtle protein variants.

Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system

Provided are methods of identifying Metabolic Syndrome phenotypes for an organism or a biological sample derived therefrom which methods are based on detecting a polymorphism, haplotype, haplotype group, or haplotype subgroup in the mitochondrial genome of the organism and correlating the polymorphism or haplotype to a Metabolic Syndrome phenotype. Also provided are systems or kits for the detection of such polymorphisms or haplotypes and the correlation of the polymorphisms or haplotypes to a Metabolic Syndrome phenotype. Provided are methods of identifying a modulator of a Metabolic Syndrome phenotype and kits for the treatment of a Metabolic Syndrome phenotype.

Douglas C. Wallace

Papers

Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling

Mitochondrial Genome, Overview

Recent advances in mitochondrial genetics

Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system

Mitochondrial DNA variants associated with metabolic syndrome